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LRRK2-Related Parkinson Disease

Synonyms: LRRK2-Associated Parkinson Disease, PARK8

, BSc, , PhD, , PhD, and , PhD.

Author Information

Initial Posting: ; Last Update: December 11, 2014.


Clinical characteristics.

LRRK2-related Parkinson disease (PD) is characterized by features consistent with PD of other etiologies: initial motor features of slowly progressive asymmetric tremor at rest and/or bradykinesia, cog-wheel muscle rigidity, postural instability, and gait abnormalities that may include festination and freezing. Non-motor symptoms in LRRK2-related PD occur with similar frequency as observed in typical PD of other etiologies. Onset is generally after age 50 years.


The diagnosis of LRRK2-related PD relies on clinical findings and the identification of a pathogenic variant in LRRK2.


Treatment of manifestations: Pharmacologic replacement of dopamine, most commonly accomplished with the precursor of dopamine, L-dopa, combined with carbi-dopa. Dopamine agonists may also be used, as well as inhibitors of catechol-O-methyltransferase (COMT) or monoamine oxidase-B (MAO-B). Physical, occupational, and speech therapy may help. Neurosurgical procedures, such as deep brain stimulation of the subthalamic nucleus/globus pallidus interna or pallido-pontine nucleus, benefit some individuals in whom dyskinesias or gait disorders are especially problematic. Less commonly pallidotomy, or rarely fetal brain transplant to the caudate nucleus, may also provide benefit.

Prevention of secondary complications: Prevention of L-dopa induced dyskinesias may include deep-brain stimulation, constant drug delivery/stimulation (CDD/CDS), reduction of levodopa doses, and the use of dopamine receptor agonists.

Surveillance: Annual neurologic examination to assess gait, tremor, rigidity, cognition and mood.

Agents/circumstances to avoid: Neuroleptic treatment may exacerbate parkinsonism.

Genetic counseling.

LRRK2-related PD is inherited in an autosomal dominant manner. However, given the reduced penetrance associated with LRRK2-related PD, a high percentage of affected individuals report unaffected parents. De novo mutation may occur; its frequency is unknown. Each child of an individual with LRRK2-related Parkinson disease has a 50% chance of inheriting the pathogenic variant. However, the risk of developing disease is lower than 50% because of age-related penetrance. Prenatal diagnosis for pregnancies at increased risk is possible if the pathogenic variant in the family is known.


Clinical Diagnosis

The diagnosis of LRRK2-related Parkinson disease (PD) relies on clinical findings and the identification of a pathogenic variant in LRRK2.

Clinical findings

Molecular Genetic Testing

Gene. LRRK2, encoding leucine-rich repeat serine/threonine-protein kinase 2, is the only gene in which pathogenic variants are known to cause LRRK2-related PD.

Table 1.

Molecular Genetic Testing Used in LRRK2-Related Parkinson Disease

Gene 1Test MethodProportion of Probands with a Pathogenic Variant Detectable by This Method
LRRK2Targeted analysis for pathogenic variants 2Varies by ethnicity
Sequence analysis 3, 4~100% 5
Deletion/duplication analysis 6, 7Unknown, none reported 7

See Table A. Genes and Databases for chromosome locus and protein. See Molecular Genetics for information on allelic variants detected in this gene.


Testing panel may vary by laboratory. Some panels may include less penetrant pathogenic variants (twofold risk) specific to Asian communities, including p.Arg1628Pro and p.Gly2385Arg which are also seen in >1% of the healthy population. At least seven variants are known to be pathogenic (see Table 3, Tables 4-5 [pdf]) [Paisán-Ruíz et al 2004, Zimprich et al 2004, Di Fonzo et al 2005, Gilks et al 2005, Kachergus et al 2005, Nichols et al 2005, Di Fonzo et al 2006b, Ross et al 2008, Aasly et al 2010]. Variant detection rates vary by ethnicity.


Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.


Other LRRK2 substitutions including p.Arg1441His, p.Ala1442Pro, and p.Ile2012Thr are likely to be pathogenic. LRRK2 p.Asn1437His, albeit rare, is another likely pathogenic variant. Two risk factors (p.Arg1628Pro and p.Gly2385Arg) have been confirmed in Asian populations [Di Fonzo et al 2006b, Tomiyama et al 2006, Farrer et al 2007, Tan et al 2007, Lu et al 2008, Ross et al 2008, Tan et al 2008]. At least 250 other coding variants have been observed, with at least 80 leading to nonsynonymous amino acid substitutions. The most frequent LRRK2 exon variants have been described in worldwide case-control series, and many have been assigned as contributing to risk or protection from Parkinson disease [Ross et al 2011].


LRRK2-related PD is defined by the presence of a pathogenic variant in LRRK2; thus the variant detection rate approaches 100% for nucleotide changes, small deletions/insertions, and mutation in splice site consensus motifs.


Testing that identifies exon or whole-gene deletions/duplications not detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA. Included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.


To date, no deletions or duplications involving LRRK2 have been reported to cause LRRK2-related Parkinson disease [Mata et al 2005a, Di Fonzo et al 2006a].

Testing Strategy

To confirm/establish the diagnosis in a proband. A diagnosis of LRRK2-related Parkinson disease is confirmed when an individual has one of the known LRRK2 pathogenic variants.

One genetic testing strategy is molecular genetic testing of LRRK2 only.

  • Given the population-specific nature of LRRK2 variants and the large number of exons that need to be sequenced, it may be cost-effective to begin with targeted analysis for pathogenic variants based on ethnicity:
    • p.Arg1441Gly appears to be restricted to those with Spanish or Hispanic ancestors.
    • p.Gly2019Ser should be tested first in those of Jewish or North African Berber ancestry.
    • p.Arg1441Cys is most frequent in those with Belgian ancestry.
    • p.Arg1628Pro and p.Gly2385Arg are only prevalent in individuals of Asian ancestry.
    • Other, rarer LRRK2 variants appear to have more global distribution.
  • If targeted analysis does not identify the ethnic-specific pathogenic variant or if ethnicity is unknown, sequence analysis of the entire coding region should be performed starting with exons encoding the Roc, COR and kinase domains.

An alternative genetic testing strategy is use of a multigene panel that includes LRRK2 and other genes of interest (see Differential Diagnosis).

Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.

For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Clinical Characteristics

Clinical Description

LRRK2-related Parkinson disease (PD) is characterized by features consistent with PD of other etiologies: initial motor features of asymmetric tremor at rest and/or bradykinesia, cog-wheel muscle rigidity, postural instability, and gait abnormalities including festination and freezing.

Onset is insidious and the disease course is slowly progressive. Age at onset is variable, even within a family. The mean age at onset is approximately 60 years, typical of late-onset Parkinson disease. The reported range in age of onset is 28 to 82 years [Ishihara et al 2006, Kay et al 2006, Trinh et al 2014b]. Men and women are affected equally.

Non-motor symptoms in LRRK2-related PD, seen as frequently as in typical PD of other etiologies, may include constipation, seborrhea, hyposmia/anosmia, sympathetic denervation of the heart, disorders of mood (apathy, depression), cognitive decline, dementia, and sleep disorders. They may appear prior to the movement disorder or emerge with motor disease progression. Constipation, mood disorders, olfactory dysfunction and sleep disorders are potential preclinical markers of PD. Virtually all individuals with PD demonstrate some sleep disruption, from excessive daytime sleepiness to REM-sleep behavior disorder, which may manifest very early in the disease course. Mild cognitive impairment and dementia may occur later in the disease. Depression is quite common and can occur in up to 40% of affected individuals [Chaudhuri et al 2006, Langston 2006].

Most studies have shown comparable clinical features in individuals with LRRK2-related PD and those with PD of other etiologies [Alcalay et al 2013]. However, REM sleep behavior disorder and gastrointestinal dysfunction have been reported to be less severe in a large cohort of individuals of Tunisian Arab-Berber descent with the p.Gly2019Ser pathogenic variant in LRRK2 compared to those with PD of other etiologies [Trinh et al 2014a].

Seven members of one family (the "Lincolnshire kindred," in which the pathogenic variant p.Tyr1699Cys segregates) presented with a behavioral disorder characterized by depression and anxiety [Khan et al 2005]. The initial family identified with the p.Tyr1699Cys pathogenic variant (Family A) [Zimprich et al 2004] also presented with atypical symptoms of dementia and amyotrophy.

Cognitive impairment does not appear to be more common in LRRK2-related PD than in typical sporadic disease; however, one report of individuals with the p.Gly2019Ser pathogenic variant suggested that Mini-Mental State Examination scores were lower than expected [Lesage et al 2005]. These findings, however, do not reflect the vast majority of individuals with LRRK2-related PD and further clinical studies suggest that cognitive impairment may occur less frequently in individuals heterozygous for the p.Gly2019Ser variant [Healy et al 2008]. Subsequent studies showed that those with LRRK2-related PD have cognitive impairment comparable to that associated with PD of other etiologies [Alcalay et al 2013, Estanga et al 2014].


  • Brain CT and MRI are normal.
  • Positron emission tomography (PET) associated with the LRRK2 pathogenic variants p.Gly2019Ser, p.Tyr1699Cys, and p.Arg1441Cys shows significant reduction in 18F-dopa uptake compared to controls; as is typical of late-onset PD, the reduced uptake is asymmetric with a rostrocaudal gradient and the putamen more affected than the caudate [Adams et al 2005, Hernandez et al 2005, Khan et al 2005, Paisán-Ruíz et al 2005]. Comparable reduction in uptake may also be observed for the presynaptic membrane dopamine transporter (SLCA3) and vesicular monoamine transporter (SLC18A2) [Adams et al 2005]. Similar findings may be seen in asymptomatic individuals with one of the same LRRK2 pathogenic variants [Adams et al 2005]. In a recent study of a LRRK2 kindred with the p.Arg1441Cys pathogenic variant, PET studies with a variety of pre- and postsynaptic tracers revealed progressive dopaminergic dysfunction in motor-impaired affected individuals as well as young asymptomatic heterozygotes [Nandhagopal et al 2008].

Neuropathology. The hallmark pathologic features of the common form of PD are neuronal loss and gliosis in the substantia nigra and the presence of intracytoplasmic inclusions (or Lewy bodies). The majority of individuals with LRRK2-related PD exhibit these characteristics [Ross et al 2006]. However, LRRK2-related PD has also been documented with four alternate pathologies including the following [Wszolek et al 2004, Zimprich et al 2004, Funayama et al 2005, Ross et al 2006, Covy et al 2009, Ujiie et al 2012]:

  • Nigral neuronal loss and gliosis without Lewy body inclusions
  • Neurofibrillary tangles
  • Ubiquitin-immunopositive inclusions (Marinesco bodies)
  • TDP-43 inclusions

Immunostaining for Lrrk2 protein has also been reported within inclusion bodies including Lewy pathology, although the specificity of the antibodies used for immunohistochemistry has not been confirmed [Giasson et al 2006, Miklossy et al 2006, Biskup et al 2007, Higashi et al 2007, Alegre-Abarrategui et al 2008, Perry et al 2008].

LRRK2-related PD has the potential to be the "Rosetta stone" of parkinsonian disorders because: (1) all the major pathologies associated with parkinsonism have been observed; and (2) the end-stage pathology may differ even in families with the same pathogenic variant (see Table 2). For example:

  • p.Arg1441Cys. Four members of Family D with this pathogenic variant had variable, pleomorphic pathology:
    • One with diffuse Lewy body disease within the cortex and brain stem;
    • One with Lewy bodies restricted to brain stem, typical of PD of other etiologies;
    • One with a 4R-tauopathy with globose neurofibrillary tangles and tufted astrocytes, reminiscent of argyrophilic grains disease and progressive supranuclear palsy (PSP); and
    • One with nigral neuronal degeneration and gliosis, without coexisting pathology [Wszolek et al 2004].
  • p.Tyr1699Cys. Two members of Family A with this pathogenic variant had ubiquitin-immunoreactive cytoplasmic and nuclear inclusions (Marinesco bodies), and a third had brain stem Lewy body disease [Zimprich et al 2004].
  • p.Gly2019Ser. As the most common pathogenic variant, p.Gly2019Ser is present in the majority of autopsied cases, in which brain stem or transitional, α-synuclein immunopositive Lewy body pathology is observed [Taylor et al 2006]. Rarely, however, nigral neuronal loss and gliosis only or alternate tauopathy or ubiquitin-immunopositive pathology are observed [Giasson et al 2006, Ross et al 2006] (see Table 2).
  • p.Ile2020Thr. In four members of the Sagamihara kindred with this pathogenic variant only moderate nigral neuronal degeneration and gliosis with no coexisting intracytoplasmic lesion pathology were observed [Funayama et al 2005]. Tau pathology has since been present in six individuals with this pathogenic variant [Ujiie et al 2012].

Table 2.

Number of Individuals with LRRK2-Related PD with Distinct Pathogenic Findings

LRRK2 Pathogenic VariantLewy Bodies and NeuritesTau and NFTsUbiquitinNeuronal Loss Only

NFTs=neurofibrillary tangles

In some cases with neuronal loss and otherwise nonspecific findings, TDP-43 immunopositive inclusions may be observed [Covy et al 2009; Dennis Dickson, personal communication].

Genotype-Phenotype Correlations

Although previously no certain correlations between specific LRRK2 pathogenic variants and age at onset, clinical presentation, or disease progression had been found [Haugarvoll et al 2008, Healy et al 2008, Hulihan et al 2008], larger cohorts have shown that in Ashkenazi Jewish populations, individuals heterozygous for the LRRK2 p.Gly2019Ser pathogenic variant are more likely to have postural instability and gait disorders [Alcalay et al 2013]. Furthermore, disease progression in p.Gly2019Ser heterozygotes appears to be uniform regardless of age at onset [Trinh et al 2014b]. Neuropathologic correlations are noted in Table 2.

"Dardarin," the Basque word for tremor, was initially proposed as a name for the protein encoded by LRRK2, leucine-rich repeat serine/threonine-protein kinase 2 (Lrrk2) to highlight excessive tremor in families from this region with the p.Arg1441Gly pathogenic variant; however, individuals with this pathogenic variant may also present with bradykinesia [Paisán-Ruíz et al 2004, Mata et al 2005b].


Penetrance of LRRK2 pathogenic variants is age dependent but may vary depending on pathogenic variant and population ethnicity.

In population-based studies, Ozelius et al [2006] determined the lifetime penetrance of p.Gly2019Ser parkinsonism by two methods:

  • Comparing the frequency of individuals with the p.Gly2019Ser pathogenic variant among individuals with PD vs. unrelated controls (penetrance: 35.2%); and
  • Calculating the proportion of the parents of these individuals diagnosed with PD (penetrance: 31.8%). This estimate is similar to that provided by Goldwurm et al [2007].

The lifetime penetrance in the Tunisian Arab-Berber population in which p.Gly2019Ser is most frequent is 45% [Hulihan et al 2008]. However, as penetrance is a function of age, it may be more meaningfully defined as an age-associated cumulative risk. In an Arab-Berber sample with the p.Gly2019Ser pathogenic variant, the symptoms of parkinsonism manifest in fewer than 20% of heterozygotes younger than age 50 years but in more than 80% of those age 70 years and older. In this population the odds ratio of disease in those heterozygous for the p.Gly2019Ser variant is 22.6 (95% CI 10.2-50.1) [Hulihan et al 2008]. The risk to heterozygotes and rarer homozygotes is equivalent [Ishihara et al 2006].

In contrast, analysis of multiplex families (i.e., families with >1 affected individual) identified a higher lifetime penetrance estimate of around 67% compared to the estimate for simplex cases [Kachergus et al 2005, Healy et al 2008, Latourelle et al 2008]. The initial study for LRRK2 p.Gly2019Ser suggests that the probability of a heterozygote manifesting symptoms is lower than 20% at age 50 years and increases in an almost linear fashion to more than 80% at age 75 years [Kachergus et al 2005]. The most recent study suggests that the risk of manifesting disease is about 8% at age 50 years but greater than 55% at 75 years [Latourelle et al 2008]. However, asymptomatic p.Gly2019Ser heterozygotes older than age 80 years have been reported [Kay et al 2005, Carmine Belin et al 2006].

More recently, gender has been shown to influence the cumulative incidence of symptom development in individuals heterozygous for a LRRK2 pathogenic variant, with females becoming affected a median of five years earlier than males [Cilia et al 2014, Trinh et al 2014a].

Ethnic background may also be a factor in penetrance. Norwegians showed a significantly reduced cumulative incidence estimate compared to Tunisian Arab Berbers. However, Israeli Ashkenazi Jewish individuals heterozygous for the LRRK2 p.Gly2019Ser pathogenic variant had comparable estimates to Tunisian Arab Berbers [Hentati et al 2014, Trinh et al 2014a]. Curiously, penetrance in a New York Ashkenazi Jewish cohort is even more reduced than in a cohort of individuals from Norway [Clark et al 2006]. While bias in ascertainment and reporting likely contributes to this figure, the identification of genetic and/or environmental modifiers of penetrance and disease susceptibility are currently under investigation.

Penetrance estimates for LRRK2 p.Gly2019Ser are most widely reported, but pedigree-based figures for p.Arg1441Cys are similar [Haugarvoll et al 2008].


Anticipation is a phenomenon whereby the symptoms of a genetic disorder become apparent at an earlier age as it is passed on to the next generation. In most cases, an increase of severity of symptoms is also noted. This usually occurs with unstable repeat disorders, e.g., Huntington disease. Anticipation has not been documented in LRRK2-related PD and is unlikely, although suggested in a few families [Khan et al 2005].


The term PARK8 refers to the chromosomal region of 12q12 linked to disease in a large Japanese PD kindred [Funayama et al 2002]. Once the associated gene and the specific pathogenic variant were identified, the term became superfluous.

The Basque word for tremor, "dardarin," has been used to refer to LRRK2-related PD cause by the pathogenic p.Arg1441Gly variant.


In the US, LRRK2-related Parkinson disease causes approximately 1.0% of simplex PD (i.e. single occurrences in a family) and approximately 5%-6% of familial PD.

LRRK2 p.Gly2019Ser is the most common pathogenic variant, accounting for the following:

These frequencies have largely been extrapolated from clinic and/or community-based series, but in the US they are in close agreement with incidence-based samples [unpublished data].

Asymptomatic heterozygotes (including 1 person age 91 years) are noted within families, typically ascertained via an affected proband [Gaig et al 2006]; however, pathogenic LRRK2 variants have negligible frequency in age-/gender-matched population controls [Kachergus et al 2005, Mata et al 2005a, Hulihan et al 2008]. Among unselected individuals of Ashkenazi Jewish ancestry, the prevalence of p.Gly2019Ser is likely 1%-2% [Ozelius et al 2006, Saunders-Pullman et al 2006].

The p.Arg1441Gly pathogenic variant, present in approximately 8% of individuals with PD from the Basque community in northern Spain, probably represents a founder variant as it has not been reported outside of Spanish-speaking communities [Paisán-Ruíz et al 2004, Mata et al 2005b, Deng et al 2006, Simón-Sánchez et al 2006, González-Fernández et al 2007, Mata et al 2009]. It is estimated that the most recent common ancestor lived 1350 (95% CI, 1020-1740) years ago (~7th century), suggesting that p.Arg1441Gly originated in the Basque population and that dispersion of the pathogenic variant then occurred through short-range gene flow that was largely limited to nearby regions in Spain [Mata et al 2009].

Differential Diagnosis

Parkinson disease multigene panels may include testing for a number of genes associated with disorders in the differential diagnosis for LRRK2-related Parkinson disease (PD). See Parkinson Disease Overview.

LRRK2-related Parkinson disease (PD) is indistinguishable from PD of unknown cause (see Parkinson Disease Overview). However, molecular genetic testing provides a definitive diagnosis.


Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with LRRK2-related Parkinson disease (PD), neurologic examination should include assessment of the following:

  • Tremor
  • Rigidity
  • Bradykinesia
  • Gait
  • Mental status

Consultation with a clinical geneticist and/or genetic counselor may also be considered.

Treatment of Manifestations

The treatment of individuals with LRRK2-related PD does not differ from that of PD of other etiologies.

The mainstay of treatment is pharmacologic replacement of dopamine, most commonly accomplished with the precursor of dopamine, L-dopa, combined with carbi-dopa.

Dopamine agonists may also be used, as well as inhibitors of catechol-O-methyltransferase (COMT) or monoamine oxidase-B (MAO-B).

The motor impairment generally responds well to dopamine therapy (agonists and levodopa).

Other medications include anticholinergics, selegiline, and amantadine [Lang & Lozano 1998a, Lang & Lozano 1998b, Hristova & Koller 2000, Marjama-Lyons & Koller 2001, Olanow & Stocchi 2004].

Neurosurgical procedures such as deep brain stimulation of the subthalamic nucleus/globus pallidus interna or pallido-pontine nucleus benefit some individuals in whom dyskinesias or gait disoders are especially problematic. Less commonly, pallidotomy (or, rarely, fetal brain transplant to the caudate nucleus) may also provide benefit [Esselink et al 2004, Schüpbach et al 2007, Gómez-Esteban et al 2008, Munhoz et al 2009].

Individuals with Parkinson disease may benefit from physical, occupational, and speech therapy.

To date, limited effective treatment exists for non-motor findings, which can be extremely disabling.

Prevention of Secondary Complications

The most common complication from L-dopa therapy is dyskinesias, for which deep-brain stimulation has proven helpful [Aasly et al 2005, Gosal et al 2005, Hernandez et al 2005, Goldwurm et al 2006, Ishihara et al 2006, Tomiyama et al 2006].

Other preventions for L-dopa induced dyskinesias include constant drug delivery/stimulation (CDD/CDS) [Jenner 2008], reduction of levodopa doses [Goetz et al 1982] and the use of dopamine receptor agonists [Holloway & Frank 2004, Holloway et al 2004].


Annual neurologic examination should assess gait, tremor, rigidity, cognition, and mood.

Agents/Circumstances to Avoid

Neuroleptic treatment may exacerbate parkinsonism in LRRK2-related PD, as in PD in general.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Lrrk2 protein is a fusion of Rab (Roc), COR and kinase (MAPK) domains, and pathogenic variants are postulated to augment kinase activity [Kachergus et al 2005, West et al 2005, Gloeckner et al 2006, Greggio et al 2006]. Hence, the development of specific kinase inhibitors offers an attractive therapeutic target for neuroprotection in asymptomatic and affected LRRK2 heterozygotes, and for PD of other etiologies [Albrecht 2005, Toft et al 2005]. A number of inhibitors are being developed; however, selectivity, specificity, and delivery into the central nervous system remain difficult issues to address [Lee et al 2010b]. Moreover, LRRK2 kinase inhibition may lead to complications that affect the lung and kidney [Herzig et al 2011].

Search in the US and in Europe for access to information on clinical studies for a wide range of diseases and conditions.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

LRRK2-related Parkinson disease (PD) is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

  • Individuals with LRRK2-related Parkinson disease have one parent who has a LRRK2 pathogenic variant. However, given the reduced penetrance associated with LRRK2-related PD, a high percentage of affected individuals report unaffected parents.
  • The probability that an asymptomatic parent with a pathogenic variant will become symptomatic increases with age.
  • If the pathogenic variant found in the proband cannot be detected in leukocyte DNA of either parent, two possible explanations are germline mosaicism in a parent or a de novo pathogenic variant in the proband.
    • Although no instances of germline mosaicism have been reported, it remains a possibility.
    • De novo pathogenic variants may occur; thus far they have not been described. Some sites within the gene may be highly mutable, notably the arginine codon at residue 1441, in which three amino acid changes have been reported to be pathogenic.

Note: Even if an individual diagnosed with LRRK2-related PD has a parent who has the LRRK2 pathogenic variant, the family history may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, reduced penetrance, or late onset of the disease in the affected parent.

Sibs of a proband

  • The risk to the sibs of the proband depends on the genetic status of the proband's parents.
  • If a parent of the proband is affected or has a pathogenic variant, the risk to the sibs of inheriting the pathogenic variant is 50%. However, the risk to sibs of developing disease is lower than 50% because of age-related penetrance (see Penetrance).
  • The probability that an asymptomatic sib who has the pathogenic variant will become symptomatic increases with age.

Offspring of a proband

  • Each child of an individual with LRRK2-related PD has a 50% chance of inheriting the pathogenic variant.
  • The probability that an offspring with a pathogenic variant will become symptomatic increases with age.

Other family members of a proband

  • The risk to other family members depends on the status of the proband's parents.
  • If a parent is affected or has a pathogenic variant, his or her family members may be at risk.

Related Genetic Counseling Issues

Testing of at-risk asymptomatic adult relatives of individuals with LRRK2-related PD is possible after molecular genetic testing has identified the specific pathogenic variant in the family. Such testing should be performed in the context of formal genetic counseling and is not useful in predicting age of onset, severity, type of symptoms, or rate of progression in asymptomatic individuals.

Testing of asymptomatic at-risk individuals with nonspecific or equivocal symptoms is predictive testing, not diagnostic testing. At-risk asymptomatic adult family members may seek testing in order to make personal decisions regarding reproduction, financial matters, and career planning. Others may have different motivations including simply the "need to know." Testing of asymptomatic at-risk adult family members usually involves pre-test interviews in which the motives for requesting the test, the individual's knowledge of LRRK2-related PD, the possible impact of positive and negative test results, and neurologic status are assessed. Those seeking testing should be counseled about possible problems that they may encounter with regard to health, life, and disability insurance coverage, employment and educational discrimination, and changes in social and family interaction. Other issues to consider are implications for the at-risk status of other family members. Informed consent should be procured and records kept confidential. Individuals with a positive test result need arrangements for long-term follow up and evaluations.

Testing of asymptomatic individuals younger than age 18 years who are at risk for adult-onset disorders for which no treatment exists is not considered appropriate, primarily because it negates the autonomy of the child with no compelling benefit. Further, concern exists regarding the potential unhealthy adverse effects that such information may have on family dynamics, the risk of discrimination and stigmatization in the future, and the anxiety that such information may cause.

In a family with an established diagnosis of LRRK2-related PD, it is appropriate to consider testing of symptomatic individuals regardless of age.

See also the National Society of Genetic Counselors position statement on genetic testing of minors for adult-onset conditions and the American Academy of Pediatrics and American College of Medical Genetics and Genomics policy statement: ethical and policy issues in genetic testing and screening of children.

Considerations in families with an apparent de novo pathogenic variant. When neither parent of a proband with an autosomal dominant condition has the pathogenic variant or clinical evidence of the disorder, it is likely that the proband has a de novo LRRK2 pathogenic variant. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy. Similarly, decisions about testing to determine the genetic status of at-risk asymptomatic family members are best made before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Once the LRRK2 pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis for LRRK2-related PD are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider decisions regarding prenatal testing to be the choice of the parents, discussion of these issues is appropriate.


GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • American Parkinson Disease Association (APDA)
    135 Parkinson Avenue
    Staten Island NY 10305
    Phone: 800-223-2732 (toll-free); 718-981-8001
    Fax: 718-981-4399
  • Fox Trial Finder
  • Michael J. Fox Foundation for Parkinson's Research
    Church Street Station
    PO Box 780
    New York NY 10008-0780
    Phone: 800-708-7644 (toll-free)
  • National Library of Medicine Genetics Home Reference
  • Parkinson's Foundation
    200 SE 1st Street
    Suite 800
    Miami FL 33131
    Phone: 800-4PD-INFO (473-4636)

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

LRRK2-Related Parkinson Disease: Genes and Databases

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for LRRK2-Related Parkinson Disease (View All in OMIM)


Gene structure. LRRK2 comprises 144 kb and 51 exons. There is only one transcript NM_198578.3. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. Pathogenic LRRK2 variants are listed in Table 3; see Table 3a (pdf) for additional information (exon, domain, and rs#).

As the pathogenicity of many LRRK2 variants has not been determined to date, other known variants are listed as nonsynonymous and silent allelic variants. See Tables 4 and 5 (pdf).

Table 3.

Selected LRRK2 Variants

Variant ClassificationDNA Nucleotide ChangePredicted Protein ChangeReference Sequences
Pathogenicc.4309A>Cp.Asn1437His 1NM_198578​.3
c.4322G>Ap.Arg1441His 2
c.4883G>Cp.Arg1628Pro 3
c.7153G>Ap.Gly2385Arg 3
Likely pathogenicc.4324G>Cp.Ala1442Pro

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​ See Quick Reference for an explanation of nomenclature.


Less penetrant pathogenic variants (2-fold risk) specific to Asian communities that are also common; >1% in the healthy population

Genetic risk factors. Recent large genome-wide association studies have shown the LRRK2 locus to contain population-based common risk factors for disease, as previously highlighted by p.Arg1628Pro and p.Gly2385Arg [Nalls et al 2011, Lill et al 2012].

A large collaborative effort by the Genetic Epidemiology of Parkinson’s Disease consortium (GEO-PD) that included investigators from 23 sites representing 15 countries on five continents examined the role of LRRK2 coding variants. Investigators contributed clinical samples on 15,540 individuals (8,611 persons with PD and 6,929 controls). The study identified two novel risk factors – p.Ala419Val in Asian populations and Met1646Thr in populations of northern European heritage – and a common LRRK2 protective haplotype (Asp551Lys-Arg1398His-Lys1423Lys), suggesting that the toxic nature of the protein can be manipulated and providing hope for future neuroprotective therapy [Tan et al 2010, Ross et al 2011].

Normal gene product. The normal gene product, leucine-rich repeat serine/threonine-protein kinase 2 (Lrrk2), is a 2527-amino acid protein (286 kd) that shares homology with the Roco family of proteins. The six conserved domains within this class of Roco proteins are: ankyrin repeat, leucine-rich repeat, Roc, COR, MAPKKK, and WD40 (see Figure 1) [Bosgraaf & Van Haastert 2003, Mata et al 2006b]. Given the size, domain composition and organization of Lrrk2, and the potential for protein-protein interactions, it is likely to be part of a higher molecular-weight complex involved in cellular signaling. Monomers of Lrrk2 protein may also dimerize, similar to the conformation adopted by most protein kinases and Ras GTPases [Gloeckner et al 2006, Dächsel et al 2007b, Deng et al 2008, Greggio et al 2008].

Figure 1. . Schematic representation of the 144-kb LRRK2 loci on chromosome 12q12.

Figure 1.

Schematic representation of the 144-kb LRRK2 loci on chromosome 12q12. The estimated start of the Lrrk2 domain structure is indicated by the residue number below the exonic-intronic (Ex1-Ex51) and domain scheme (690). Domains: ANK = ankyrin repeat region (more...)

Several biochemical studies have since confirmed kinase activity for Lrrk2 wild type protein and a number of substrates or cofactors have been nominated [West et al 2005, Gloeckner et al 2006, Greggio et al 2006, Iaccarino et al 2007]. These include threonine 558 of moesin, a member of the ERM/merlin family that links plasma membrane receptor complexes to the microfilament cytoskeleton [Jaleel et al 2007]. In Drosophila, Lrrk2 has also been shown to interact with the insulin/IGF signaling pathway to enhance 4E-BP phosphorylation at theonine 37/46, a negative regulator of eIF4E-mediated protein translation that is critical in stress response and dopaminergic neuronal maintenance [Imai et al 2008]. Whether these are true substrates in vivo has yet to be demonstrated, as does their relevance to PD.

Several groups have shown that Lrrk2 GTP binding and GTPase activity have a modifying effect on kinase activity [Guo et al 2007, Lewis et al 2007, Li et al 2007, van Egmond et al 2008]. The Roc-COR domain may also require dimerization for optimal GTPase activity [Deng et al 2008, Gotthardt et al 2008, Greggio et al 2008].

Abnormal gene product. It is postulated that mutated leucine-rich repeat serine/threonine-protein kinase 2 proteins augment MAPK activity, resulting in a toxic gain of function; experimental data now provide some support for this pathogenic mechanism [Smith et al 2005, Greggio et al 2006, Mata et al 2006b].

Lrrk2 p.Gly2019Ser is within exon 41 and the "activation hinge" of the MAPK domain and is associated with a two- to threefold increase of intra- and intermolecular phosphorylation [West et al 2005, Greggio et al 2006, MacLeod et al 2006, Smith et al 2006, Jaleel et al 2007, Luzón-Toro et al 2007, Anand et al 2009]. Whether enhanced kinase activity in vivo represents a characteristic feature shared by all pathogenic Lrrk2 variants remains controversial [Jaleel et al 2007, Anand et al 2009]. The Lrrk2 p.Ile2020Thr substitution and the adjacent p.Gly2019Ser also both provide a potential site for phosphorylation [Zimprich et al 2004, Funayama et al 2005]. Lrrk2 p.Arg1441Cys, Gly, and His substitutions affect the same arginine residue in the Roc domain, a "Ras-like" part of the protein, that binds and hydrolyses GTP and appears to be a prerequisite for Lrrk2 kinase activity [Mata et al 2006b, Ito et al 2007, Lewis et al 2007, Greggio et al 2008]. Lrrk2 p.Arg1628Pro and p.Tyr1699Cys are located within the COR domain that bridges Roc and MAPK domains, whereas p.Gly2385Arg is located on the external surface of the C-terminal WD40 "barrel," a motif with multiple binding surfaces that usually facilitates protein-protein interactions [Mata et al 2006b].

In retinoic acid-differentiated SH-SY5Y, primary neuronal cultures, and in the intact rodent CNS the overexpression of Lrrk2 mutants induces a progressive reduction in neuritic length and branching [MacLeod et al 2006, Plowey et al 2008, Dächsel et al 2010]. In contrast, Lrrk2 knockdown induced by RNA interference, or overexpression of a Lrrk2 variant with deficient kinase activity, confers increased neuritic length and branching [MacLeod et al 2006]. In the same model, expression of pathogenic Lrrk2 variants linked to PD may lead to prominent phospho-tau immuno-positive inclusions, with lysosomal characteristics, concomitant with apoptosis [MacLeod et al 2006]. A BAC mouse model overexpressing the human LRRK2 p.Arg1441Gly pathogenic variant has been reported to have a deficit in dopamine release, a progressive movement disorder leading to akinesia, and tau pathology [Li et al 2009].

Recent studies have implicated mutated LRRK2 in a number of different pathways including autophagy, endosomal-lysosomal function, and Wnt signaling [Berwick & Harvey 2011, Berwick & Harvey 2012, Friedman et al 2012, Gómez-Suaga & Hilfiker 2012, Tong et al 2012, Bravo-San Pedro et al 2013].

LRRK2 has also been shown to play an important function at the synapse and may play a role in vesicle recycling [Lee et al 2010a, Piccoli et al 2011]. LRRK2 p.Gly2019Ser has been shown to increase the probability of striatal glutamate release [Beccano-Kelly et al 2015].


Published Guidelines / Consensus Statements

  • Committee on Bioethics, Committee on Genetics, and American College of Medical Genetics and Genomics Social, Ethical, Legal Issues Committee. Ethical and policy issues in genetic testing and screening of children. Available online. 2013. Accessed 7-25-18 [PubMed: 23428972]
  • National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset disorders. Available online. 2017. Accessed 7-25-18.

Literature Cited

  • Aasly JO, Toft M, Fernandez-Mata I, Kachergus J, Hulihan M, White LR, Farrer M. Clinical features of LRRK2-associated Parkinson's disease in central Norway. Ann Neurol. 2005;57:762–5. [PubMed: 15852371]
  • Aasly JO, Vilariño-Güell C, Dachsel JC, Webber PJ, West AB, Haugarvoll K, Johansen KK, Toft M, Nutt JG, Payami H, Kachergus JM, Lincoln SJ, Felic A, Wider C, Soto-Ortolaza AI, Cobb SA, White LR, Ross OA, Farrer MJ. Novel pathogenic LRRK2 p.Asn1437His substitution in familial Parkinson's disease. Mov Disord. 2010;25:2156–63. [PMC free article: PMC2970614] [PubMed: 20669305]
  • Adams JR, van Netten H, Schulzer M, Mak E, Mckenzie J, Strongosky A, Sossi V, Ruth TJ, Lee CS, Farrer M, Gasser T, Uitti RJ, Calne DB, Wszolek ZK, Stoessl AJ. PET in LRRK2 mutations: comparison to sporadic Parkinson's disease and evidence for presymptomatic compensation. Brain. 2005;128:2777–85. [PubMed: 16081470]
  • Albrecht M. LRRK2 mutations and Parkinsonism. Lancet. 2005;365:1230. [PubMed: 15811455]
  • Alcalay RN, Mirelman A, Saunders-Pullman R, Tang MX, Mejia Santana H, Raymond D, Roos E, Orbe-Reilly M, Gurevich T, Bar Shira A, Gana Weisz M, Yasinovsky K, Zalis M, Thaler A, Deik A, Barrett MJ, Cabassa J, Groves M, Hunt AL, Lubarr N, San Luciano M, Miravite J, Palmese C, Sachdev R, Sarva H, Severt L, Shanker V, Swan MC, Soto-Valencia J, Johannes B, Ortega R, Fahn S, Cote L, Waters C, Mazzoni P, Ford B, Louis E, Levy O, Rosado L, Ruiz D, Dorovski T, Pauciulo M, Nichols W, Orr-Urtreger A, Ozelius L, Clark L, Giladi N, Bressman S, Marder KS. Parkinson disease phenotype in Ashkenazi Jews with and without LRRK2 G2019S mutations. Mov Disord. 2013;28:1966–71. [PMC free article: PMC3859844] [PubMed: 24243757]
  • Alegre-Abarrategui J, Ansorge O, Esiri M, Wade-Martins R. LRRK2 is a component of granular alpha-synuclein pathology in the brainstem of Parkinson's disease. Neuropathol Appl Neurobiol. 2008;34:272–83. [PMC free article: PMC2833010] [PubMed: 17971075]
  • Anand VS, Reichling LJ, Lipinski K, Stochaj W, Duan W, Kelleher K, Pungaliya P, Brown EL, Reinhart PH, Somberg R, Hirst WD, Riddle SM, Braithwaite SP. Investigation of leucine-rich repeat kinase 2: enzymological properties and novel assays. FEBS J. 2009;276:466–78. [PubMed: 19076219]
  • Beccano-Kelly DA, Volta M, Munsie LN, Paschall SA, Tatarnikov I, Co K, Chou P, Cao LP, Bergeron S, Mitchell E, Han H, Melrose HL, Tapia L, Raymond LA, Farrer MJ, Milnerwood AJ. LRRK2 overexpression alters glutamatergic presynaptic plasticity, striatal dopamine tone, postsynaptic signal transduction, motor activity and memory. Hum Mol Genet. 2015;24:1336–49. [PubMed: 25343991]
  • Berwick DC, Harvey K. LRRK2 functions as a Wnt signaling scaffold, bridging cytosolic proteins and membrane-localized LRP6. Hum Mol Genet. 2012;21:4966–79. [PMC free article: PMC3709196] [PubMed: 22899650]
  • Berwick DC, Harvey K. LRRK2 signaling pathways: the key to unlocking neurodegeneration? Trends Cell Biol. 2011;21:257–65. [PubMed: 21306901]
  • Biskup S, Moore DJ, Rea A, Lorenz-Deperieux B, Coombes CE, Dawson VL, Dawson TM, West AB. Dynamic and redundant regulation of LRRK2 and LRRK1 expression. BMC Neurosci. 2007;8:102. [PMC free article: PMC2233633] [PubMed: 18045479]
  • Bosgraaf L, Van Haastert PJ. Roc, a Ras/GTPase domain in complex proteins. Biochim Biophys Acta. 2003;1643:5–10. [PubMed: 14654223]
  • Bravo-San Pedro JM, Niso-Santano M, Gómez-Sánchez R, Pizarro-Estrella E, Aiastui-Pujana A, Gorostidi A, Climent V, López de Maturana R, Sanchez-Pernaute R, López de Munain A, Fuentes JM, González-Polo RA. The LRRK2 G2019S mutant exacerbates basal autophagy through activation of the MEK/ERK pathway. Cell Mol Life Sci. 2013;70:121–36. [PubMed: 22773119]
  • Carmine Belin A, Westerlund M, Sydow O, Lundströmer K, Håkansson A, Nissbrandt H, Olson L, Galter D. Leucine-rich repeat kinase 2 (LRRK2) mutations in a Swedish Parkinson cohort and a healthy nonagenarian. Mov Disord. 2006;21:1731–4. [PubMed: 16817197]
  • Chaudhuri KR, Healy DG, Schapira AH. Non-motor symptoms of Parkinson's disease: diagnosis and management. Lancet Neurol. 2006;5:235–45. [PubMed: 16488379]
  • Cilia R, Siri C, Rusconi D, Allegra R, Ghiglietti A, Sacilotto G, Zini M, Zecchinelli AL, Asselta R, Duga S, Paganoni AM, Pezzoli G, Seia M, Goldwurm S. LRRK2 mutations in Parkinson’s disease: confirmation of a gender effect in the Italian population. Parkinsonism Relat Disord. 2014;20:911–4. [PMC free article: PMC4144811] [PubMed: 24816003]
  • Clark LN, Wang Y, Karlins E, Saito L, Mejia-Santana H, Harris J, Louis ED, Cote LJ, Andrews H, Fahn S, Waters C, Ford B, Frucht S, Ottman R, Marder K. Frequency of LRRK2 mutations in early- and late-onset Parkinson disease. Neurology. 2006;67:1786–91. [PubMed: 17050822]
  • Covy JP, Yuan W, Waxman EA, Hurtig HI, Van Deerlin VM, Giasson BI. Clinical and pathological characteristics of patients with leucine-rich repeat kinase-2 mutations. Mov Disord. 2009;24:32–9. [PMC free article: PMC2634827] [PubMed: 19006185]
  • Dächsel JC, Behrouz B, Yue M, Beevers JE, Melrose HL, Farrer MJ. A comparative study of Lrrk2 function in primary neuronal cultures. Parkinsonism Relat Disord. 2010;16:650–5. [PMC free article: PMC3159957] [PubMed: 20850369]
  • Dächsel JC, Ross OA, Mata IF, Kachergus J, Toft M, Cannon A, Baker M, Adamson J, Hutton M, Dickson DW, Farrer MJ. Lrrk2 G2019S substitution in frontotemporal lobar degeneration with ubiquitin-immunoreactive neuronal inclusions. Acta Neuropathol. 2007a;113:601–6. [PubMed: 17151837]
  • Dächsel JC, Taylor JP, Mok SS, Ross OA, Hinkle KM, Bailey RM, Hines JH, Szutu J, Madden B, Petrucelli L, Farrer MJ. Identification of potential protein interactors of Lrrk2. Parkinsonism Relat Disord. 2007b;13:382–5. [PMC free article: PMC2970619] [PubMed: 17400507]
  • Deng H, Le W, Guo Y, Hunter CB, Xie W, Huang M, Jankovic J. Genetic analysis of LRRK2 mutations in patients with Parkinson disease. J Neurol Sci. 2006;251:102–6. [PubMed: 17097110]
  • Deng H, Le W, Guo Y, Hunter CB, Xie W, Jankovic J. Genetic and clinical identification of Parkinson's disease patients with LRRK2 G2019S mutation. Ann Neurol. 2005;57:933–4. [PubMed: 15929036]
  • Deng J, Lewis PA, Greggio E, Sluch E, Beilina A, Cookson MR. Structure of the ROC domain from the Parkinson's disease-associated leucine-rich repeat kinase 2 reveals a dimeric GTPase. Proc Natl Acad Sci USA. 2008;105:1499–504. [PMC free article: PMC2234173] [PubMed: 18230735]
  • Di Fonzo A, Rohe CF, Ferreira J, Chien HF, Vacca L, Stocchi F, Guedes L, Fabrizio E, Manfredi M, Vanacore N, Goldwurm S, Breedveld G, Sampaio C, Meco G, Barbosa E, Oostra BA, Bonifati V. A frequent LRRK2 gene mutation associated with autosomal dominant Parkinson's disease. Lancet. 2005;365:412–5. [PubMed: 15680456]
  • Di Fonzo A, Tassorelli C, De Mari M, Chien HF, Ferreira J, Rohe CF, Riboldazzi G, Antonini A, Albani G, Mauro A, Marconi R, Abbruzzese G, Lopiano L, Fincati E, Guidi M, Marini P, Stocchi F, Onofrj M, Toni V, Tinazzi M, Fabbrini G, Lamberti P, Vanacore N, Meco G, Leitner P, Uitti RJ, Wszolek ZK, Gasser T, Simons EJ, Breedveld GJ, Goldwurm S, Pezzoli G, Sampaio C, Barbosa E, Martignoni E, Oostra BA, Bonifati V. Comprehensive analysis of the LRRK2 gene in sixty families with Parkinson's disease. Eur J Hum Genet. 2006a;14:322–31. [PubMed: 16333314]
  • Di Fonzo A, Wu-Chou YH, Lu CS, van Doeselaar M, Simons EJ, Rohe CF, Chang HC, Chen RS, Weng YH, Vanacore N, Breedveld GJ, Oostra BA, Bonifati V. A common missense variant in the LRRK2 gene, Gly2385Arg, associated with Parkinson's disease risk in Taiwan. Neurogenetics. 2006b;7:133–8. [PubMed: 16633828]
  • Esselink RA, de Bie RM, de Haan RJ, Lenders MW, Nijssen PC, Staal MJ, Smeding HM, Schuurman PR, Bosch DA, Speelman JD. Unilateral pallidotomy versus bilateral subthalamic nucleus stimulation in PD: a randomized trial. Neurology. 2004;62:201–7. [PubMed: 14745054]
  • Estanga A, Rodriguez-Oroz MC, Ruiz-Martinez J, Barandiaran M, Gorostidi A, Bergareche A, Mondragon E, Lopez de Munain A, Marti-Masso JF. Cognitive dysfunction in Parkinson's disease related to the R1441G mutation in LRRK2. Parkinsonism Relat Disord. 2014;20:1097–100. [PubMed: 25127457]
  • Farrer M, Stone J, Mata IF, Lincoln S, Kachergus J, Hulihan M, Strain KJ, Maraganore DM. LRRK2 mutations in Parkinson disease. Neurology. 2005;65:738–40. [PubMed: 16157908]
  • Farrer MJ, Stone JT, Lin CH, Dächsel JC, Hulihan MM, Haugarvoll K, Ross OA, Wu RM. Lrrk2 G2385R is an ancestral risk factor for Parkinson's disease in Asia. Parkinsonism Relat Disord. 2007;13:89–92. [PubMed: 17222580]
  • Friedman LG, Lachenmayer ML, Wang J, He L, Poulose SM, Komatsu M, Holstein GR, Yue Z. Disrupted autophagy leads to dopaminergic axon and dendrite degeneration and promotes presynaptic accumulation of α-synuclein and LRRK2 in the brain. J Neurosci. 2012;32:7585–93. [PMC free article: PMC3382107] [PubMed: 22649237]
  • Funayama M, Hasegawa K, Kowa H, Saito M, Tsuji S, Obata F. A new locus for Parkinson's disease (PARK8) maps to chromosome 12p11.2-q13.1. Ann Neurol. 2002;51:296–301. [PubMed: 11891824]
  • Funayama M, Hasegawa K, Ohta E, Kawashima N, Komiyama M, Kowa H, Tsuji S, Obata F. An LRRK2 mutation as a cause for the parkinsonism in the original PARK8 family. Ann Neurol. 2005;57:918–21. [PubMed: 15880653]
  • Gaig C, Ezquerra M, Marti MJ, Munoz E, Valldeoriola F, Tolosa E. LRRK2 mutations in Spanish patients with Parkinson disease: frequency, clinical features, and incomplete penetrance. Arch Neurol. 2006;63:377–82. [PubMed: 16533964]
  • Giasson BI, Covy JP, Bonini NM, Hurtig HI, Farrer MJ, Trojanowski JQ, Van Deerlin VM. Biochemical and pathological characterization of Lrrk2. Ann Neurol. 2006;59:315–22. [PubMed: 16437584]
  • Gilks WP, Abou-Sleiman PM, Gandhi S, Jain S, Singleton A, Lees AJ, Shaw K, Bhatia KP, Bonifati V, Quinn NP, Lynch J, Healy DG, Holton JL, Revesz T, Wood NW. A common LRRK2 mutation in idiopathic Parkinson's disease. Lancet. 2005;365:415–6. [PubMed: 15680457]
  • Gloeckner CJ, Kinkl N, Schumacher A, Braun RJ, O'Neill E, Meitinger T, Kolch W, Prokisch H, Ueffing M. The Parkinson disease causing LRRK2 mutation I2020T is associated with increased kinase activity. Hum Mol Genet. 2006;15:223–32. [PubMed: 16321986]
  • Goetz CG, Tanner CM, Klawans HL. Drug holiday in the management of Parkinson disease. Clin Neuropharmacol. 1982;5:351–64. [PubMed: 6760963]
  • Goldwurm S, Di Fonzo A, Simons EJ, Rohe CF, Zini M, Canesi M, Tesei S, Zecchinelli A, Antonini A, Mariani C, Meucci N, Sacilotto G, Sironi F, Salani G, Ferreira J, Chien HF, Fabrizio E, Vanacore N, Dalla Libera A, Stocchi F, Diroma C, Lamberti P, Sampaio C, Meco G, Barbosa E, Bertoli-Avella AM, Breedveld GJ, Oostra BA, Pezzoli G, Bonifati V. The G6055A (G2019S) mutation in LRRK2 is frequent in both early and late onset Parkinson's disease and originates from a common ancestor. J Med Genet. 2005;42:e65. [PMC free article: PMC1735940] [PubMed: 16272257]
  • Goldwurm S, Zini M, Di Fonzo A, De Gaspari D, Siri C, Simons EJ, van Doeselaar M, Tesei S, Antonini A, Canesi M, Zecchinelli A, Mariani C, Meucci N, Sacilotto G, Cilia R, Isaias IU, Bonetti A, Sironi F, Ricca S, Oostra BA, Bonifati V, Pezzoli G. LRRK2 G2019S mutation and Parkinson's disease: A clinical, neuropsychological and neuropsychiatric study in a large Italian sample. Parkinsonism Relat Disord. 2006;12:410–9. [PubMed: 16750929]
  • Goldwurm S, Zini M, Mariani L, Tesei S, Miceli R, Sironi F, Clementi M, Bonifati V, Pezzoli G. Evaluation of LRRK2 G2019S penetrance: relevance for genetic counseling in Parkinson disease. Neurology. 2007;68:1141–3. [PubMed: 17215492]
  • Gómez-Esteban JC, Lezcano E, Zarranz JJ, González C, Bilbao G, Lambarri I, Rodríguez O, Garibi J. Outcome of bilateral deep brain subthalamic stimulation in patients carrying the R1441G mutation in the LRRK2 dardarin gene. Neurosurgery. 2008;62:857–62. [PubMed: 18496192]
  • González-Fernández MC, Lezcano E, Ross OA, Gómez-Esteban JC, Gómez-Busto F, Velasco F, Alvarez-Alvarez M, Rodríguez-Martínez MB, Ciordia R, Zarranz JJ, Farrer MJ, Mata IF, de Pancorbo MM. Lrrk2-associated parkinsonism is a major cause of disease in Northern Spain. Parkinsonism Relat Disord. 2007;13:509–15. [PubMed: 17540608]
  • Gómez-Suaga P, Hilfiker S. LRRK2 as a modulator of lysosomal calcium homeostasis with downstream effects on autophagy. Autophagy. 2012;8:692–3. [PubMed: 22441017]
  • Gosal D, Ross OA, Wiley J, Irvine GB, Johnston JA, Toft M, Mata IF, Kachergus J, Hulihan M, Taylor JP, Lincoln SJ, Farrer MJ, Lynch T, Mark Gibson J. Clinical traits of LRRK2-associated Parkinson's disease in Ireland: a link between familial and idiopathic PD. Parkinsonism Relat Disord. 2005;11:349–52. [PubMed: 16102999]
  • Gotthardt K, Weyand M, Kortholt A, Van Haastert PJ, Wittinghofer A. Structure of the Roc-COR domain tandem of C. tepidum, a prokaryotic homologue of the human LRRK2 Parkinson kinase. EMBO J. 2008;27:2239–49. [PMC free article: PMC2519104] [PubMed: 18650931]
  • Greggio E, Jain S, Kingsbury A, Bandopadhyay R, Lewis P, Kaganovich A, van der Brug MP, Beilina A, Blackinton J, Thomas KJ, Ahmad R, Miller DW, Kesavapany S, Singleton A, Lees A, Harvey RJ, Harvey K, Cookson MR. Kinase activity is required for the toxic effects of mutant LRRK2/dardarin. Neurobiol Dis. 2006;23:329–41. [PubMed: 16750377]
  • Greggio E, Zambrano I, Kaganovich A, Beilina A, Taymans JM, Daniëls V, Lewis P, Jain S, Ding J, Syed A, Thomas KJ, Baekelandt V, Cookson MR. The Parkinson disease-associated leucine-rich repeat kinase 2 (LRRK2) is a dimer that undergoes intramolecular autophosphorylation. J Biol Chem. 2008;283:16906–14. [PMC free article: PMC2423262] [PubMed: 18397888]
  • Guo L, Gandhi PN, Wang W, Petersen RB, Wilson-Delfosse AL, Chen SG. The Parkinson's disease-associated protein, leucine-rich repeat kinase 2 (LRRK2), is an authentic GTPase that stimulates kinase activity. Exp Cell Res. 2007;313:3658–70. [PMC free article: PMC2083285] [PubMed: 17706965]
  • Haugarvoll K, Rademakers R, Kachergus JM, Nuytemans K, Ross OA, Gibson JM, Tan EK, Gaig C, Tolosa E, Goldwurm S, Guidi M, Riboldazzi G, Brown L, Walter U, Benecke R, Berg D, Gasser T, Theuns J, Pals P, Cras P, De Deyn PP, Engelborghs S, Pickut B, Uitti RJ, Foroud T, Nichols WC, Hagenah J, Klein C, Samii A, Zabetian CP, Bonifati V, Van Broeckhoven C, Farrer MJ, Wszolek ZK. Lrrk2 R1441C parkinsonism is clinically similar to sporadic Parkinson disease. Neurology. 2008;70:1456–60. [PMC free article: PMC3906630] [PubMed: 18337586]
  • Healy DG, Falchi M, O'Sullivan SS, Bonifati V, Durr A, Bressman S, Brice A, Aasly J, Zabetian CP, Goldwurm S, Ferreira JJ, Tolosa E, Kay DM, Klein C, Williams DR, Marras C, Lang AE, Wszolek ZK, Berciano J, Schapira AH, Lynch T, Bhatia KP, Gasser T, Lees AJ, Wood NW, et al. Phenotype, genotype, and worldwide genetic penetrance of LRRK2-associated Parkinson's disease: a case-control study. Lancet Neurol. 2008;7:583–90. [PMC free article: PMC2832754] [PubMed: 18539534]
  • Hernandez DG, Paisán-Ruíz C, McInerney-Leo A, Jain S, Meyer-Lindenberg A, Evans EW, Berman KF, Johnson J, Auburger G, Schaffer AA, Lopez GJ, Nussbaum RL, Singleton AB. Clinical and positron emission tomography of Parkinson's disease caused by LRRK2. Ann Neurol. 2005;57:453–6. [PubMed: 15732108]
  • Herzig MC, Kolly C, Persohn E, Theil D, Schweizer T, Hafner T, Stemmelen C, Troxler TJ, Schmid P, Danner S, Schnell CR, Muelle M, Kinzel B, Grevot A, Bolognani F, Stirn M, Kuhn RR, Kaupmann K, van der Putten PH, Rovelli G, Shimshek DR. LRRK2 protein levels are determined by kinase function and are crucial for kidney and lung homeostasis in mice. Hum Mol Genet. 2011;20:4209–23. [PMC free article: PMC3188995] [PubMed: 21828077]
  • Hentati F, Trinh J, Thompson C, Nosova E, Farrer MJ, Aasly JO. LRRK2 parkinsonism in Tunisia and Norway: a comparative analysis of disease penetrance. Neurology. 2014;83:568–9. [PMC free article: PMC4142000] [PubMed: 25008396]
  • Higashi S, Biskup S, West AB, Trinkaus D, Dawson VL, Faull RL, Waldvogel HJ, Arai H, Dawson TM, Moore DJ, Emson PC. Localization of Parkinson's disease-associated LRRK2 in normal and pathological human brain. Brain Res. 2007;1155:208–19. [PubMed: 17512502]
  • Holloway R, Frank S. Review: anticholinergic drugs improve motor function and disability in Parkinson disease. ACP J Club. 2004;140:15. [PubMed: 14711286]
  • Holloway RG, Shoulson I, Fahn S, Kieburtz K, Lang A, Marek K, McDermott M, Seibyl J, Weiner W, Musch B, Kamp C, Welsh M, Shinaman A, Pahwa R, Barclay L, Hubble J, LeWitt P, Miyasaki J, Suchowersky O, Stacy M, Russell DS, Ford B, Hammerstad J, Riley D, Standaert D, Wooten F, Factor S, Jankovic J, Atassi F, Kurlan R, Panisset M, Rajput A, Rodnitzky R, Shults C, Petsinger G, Waters C, Pfeiffer R, Biglan K, Borchert L, Montgomery A, Sutherland L, Weeks C, DeAngelis M, Sime E, Wood S, Pantella C, Harrigan M, Fussell B, Dillon S, Alexander-Brown B, Rainey P, Tennis M, Rost-Ruffner E, Brown D, Evans S, Berry D, Hall J, Shirley T, Dobson J, Fontaine D, Pfeiffer B, Brocht A, Bennett S, Daigneault S, Hodgeman K, O'Connell C, Ross T, Richard K, Watts A., Parkinson Study Group. Pramipexole vs levodopa as initial treatment for Parkinson disease: a 4-year randomized controlled trial. Arch Neurol. 2004;61:1044–53. [PubMed: 15262734]
  • Hristova AH, Koller WC. Early Parkinson's disease: what is the best approach to treatment. Drugs Aging. 2000;17:165–81. [PubMed: 11043817]
  • Hulihan MM, Ishihara-Paul L, Kachergus J, Warren L, Amouri R, Elango R, Prinjha RK, Upmanyu R, Kefi M, Zouari M, Sassi SB, Yahmed SB, El Euch-Fayeche G, Matthews PM, Middleton LT, Gibson RA, Hentati F, Farrer MJ. LRRK2 Gly2019Ser penetrance in Arab-Berber patients from Tunisia: a case-control genetic study. Lancet Neurol. 2008;7:591–4. [PubMed: 18539535]
  • Iaccarino C, Crosio C, Vitale C, Sanna G, Carrì MT, Barone P. Apoptotic mechanisms in mutant LRRK2-mediated cell death. Hum Mol Genet. 2007;16:1319–26. [PubMed: 17409193]
  • Imai Y, Gehrke S, Wang HQ, Takahashi R, Hasegawa K, Oota E, Lu B. Phosphorylation of 4E-BP by LRRK2 affects the maintenance of dopaminergic neurons in Drosophila. Embo J. 2008;27:2432–43. [PMC free article: PMC2543051] [PubMed: 18701920]
  • Infante J, Rodriguez E, Combarros O, Mateo I, Fontalba A, Pascual J, Oterino A, Polo JM, Leno C, Berciano J. LRRK2 G2019S is a common mutation in Spanish patients with late-onset Parkinson's disease. Neurosci Lett. 2006;395:224–6. [PubMed: 16298482]
  • Ishihara L, Warren L, Gibson R, Amouri R, Lesage S, Durr A, Tazir M, Wszolek ZK, Uitti RJ, Nichols WC, Griffith A, Hattori N, Leppert D, Watts R, Zabetian CP, Foroud TM, Farrer MJ, Brice A, Middleton L, Hentati F. Clinical features of Parkinson disease patients with homozygous leucine-rich repeat kinase 2 G2019S mutations. Arch Neurol. 2006;63:1250–4. [PubMed: 16966502]
  • Ito G, Okai T, Fujino G, Takeda K, Ichijo H, Katada T, Iwatsubo T. GTP binding is essential to the protein kinase activity of LRRK2, a causative gene product for familial Parkinson's disease. Biochemistry. 2007;46:1380–8. [PubMed: 17260967]
  • Jaleel M, Nichols RJ, Deak M, Campbell DG, Gillardon F, Knebel A, Alessi DR. LRRK2 phosphorylates moesin at threonine-558: characterization of how Parkinson's disease mutants affect kinase activity. Biochem J. 2007;405:307–17. [PMC free article: PMC1904520] [PubMed: 17447891]
  • Jenner P. Preventing and controlling dyskinesia in Parkinson’s disease—a view of current knowledge and future opportunities. Mov Disord. 2008;23 Suppl 3:S585–98. [PubMed: 18781676]
  • Kachergus J, Mata IF, Hulihan M, Taylor JP, Lincoln S, Aasly J, Gibson JM, Ross OA, Lynch T, Wiley J, Payami H, Nutt J, Maraganore DM, Czyzewski K, Styczynska M, Wszolek ZK, Farrer MJ, Toft M. Identification of a novel LRRK2 mutation linked to autosomal dominant parkinsonism: evidence of a common founder across European populations. Am J Hum Genet. 2005;76:672–80. [PMC free article: PMC1199304] [PubMed: 15726496]
  • Kay DM, Kramer P, Higgins D, Zabetian CP, Payami H. Escaping Parkinson's disease: a neurologically healthy octogenarian with the LRRK2 G2019S mutation. Mov Disord. 2005;20:1077–8. [PubMed: 16001413]
  • Kay DM, Zabetian CP, Factor SA, Nutt JG, Samii A, Griffith A, Bird TD, Kramer P, Higgins DS, Payami H. Parkinson's disease and LRRK2: frequency of a common mutation in U.S. movement disorder clinics. Mov Disord. 2006;21:519–23. [PubMed: 16250030]
  • Khan NL, Jain S, Lynch JM, Pavese N, Abou-Sleiman P, Holton JL, Healy DG, Gilks WP, Sweeney MG, Ganguly M, Gibbons V, Gandhi S, Vaughan J, Eunson LH, Katzenschlager R, Gayton J, Lennox G, Revesz T, Nicholl D, Bhatia KP, Quinn N, Brooks D, Lees AJ, Davis MB, Piccini P, Singleton AB, Wood NW. Mutations in the gene LRRK2 encoding dardarin (PARK8) cause familial Parkinson's disease: clinical, pathological, olfactory and functional imaging and genetic data. Brain. 2005;128:2786–96. [PubMed: 16272164]
  • Lang AE, Lozano AM. Parkinson's disease. First of two parts. N Engl J Med. 1998a;339:1044–53. [PubMed: 9761807]
  • Lang AE, Lozano AM. Parkinson's disease. Second of two parts. N Engl J Med. 1998b;339:1130–43. [PubMed: 9770561]
  • Langston JW. The Parkinson's complex: parkinsonism is just the tip of the iceberg. Ann Neurol. 2006;59:591–6. [PubMed: 16566021]
  • Latourelle JC, Sun M, Lew MF, Suchowersky O, Klein C, Golbe LI, Mark MH, Growdon JH, Wooten GF, Watts RL, Guttman M, Racette BA, Perlmutter JS, Ahmed A, Shill HA, Singer C, Goldwurm S, Pezzoli G, Zini M, Saint-Hilaire MH, Hendricks AE, Williamson S, Nagle MW, Wilk JB, Massood T, Huskey KW, Laramie JM, DeStefano AL, Baker KB, Itin I, Litvan I, Nicholson G, Corbett A, Nance M, Drasby E, Isaacson S, Burn DJ, Chinnery PF, Pramstaller PP, Al-hinti J, Moller AT, Ostergaard K, Sherman SJ, Roxburgh R, Snow B, Slevin JT, Cambi F, Gusella JF, Myers RH. The Gly2019Ser mutation in LRRK2 is not fully penetrant in familial Parkinson's disease: the GenePD study. BMC Med. 2008;6:32. [PMC free article: PMC2596771] [PubMed: 18986508]
  • Lee BD, Shin JH, VanKampen J, Petrucelli L, West AB, Ko HS, Lee YI, Maguire-Zeiss KA, Bowers WJ, Federoff HJ, Dawson VL, Dawson TM. Inhibitors of leucine-rich repeat kinase-2 protect against models of Parkinson's disease. Nat Med. 2010b;16:998–1000. [PMC free article: PMC2935926] [PubMed: 20729864]
  • Lee S, Liu HP, Lin WY, Guo H, Lu B. LRRK2 kinase regulates synaptic morphology through distinct substrates at the presynaptic and postsynaptic compartments of the Drosophila neuromuscular junction. J Neurosci. 2010a;30:16959–69. [PMC free article: PMC3045823] [PubMed: 21159966]
  • Lesage S, Durr A, Tazir M, Lohmann E, Leutenegger AL, Janin S, Pollak P, Brice A. LRRK2 G2019S as a cause of Parkinson's disease in North African Arabs. N Engl J Med. 2006;354:422–3. [PubMed: 16436781]
  • Lesage S, Ibanez P, Lohmann E, Pollak P, Tison F, Tazir M, Leutenegger AL, Guimaraes J, Bonnet AM, Agid Y, Durr A, Brice A. G2019S LRRK2 mutation in French and North African families with Parkinson's disease. Ann Neurol. 2005;58:784–7. [PubMed: 16240353]
  • Lewis PA, Greggio E, Beilina A, Jain S, Baker A, Cookson MR. The R1441C mutation of LRRK2 disrupts GTP hydrolysis. Biochem Biophys Res Commun. 2007;357:668–71. [PMC free article: PMC1939973] [PubMed: 17442267]
  • Li X, Tan YC, Poulose S, Olanow CW, Huang XY, Yue Z. Leucine-rich repeat kinase 2 (LRRK2)/PARK8 possesses GTPase activity that is altered in familial Parkinson's disease R1441C/G mutants. J Neurochem. 2007;103:238–47. [PMC free article: PMC2827244] [PubMed: 17623048]
  • Li Y, Liu W, Oo TF, Wang L, Tang Y, Jackson-Lewis V, Zhou C, Geghman K, Bogdanov M, Przedborski S, Beal MF, Burke RE, Li C. Mutant LRRK2(R1441G) BAC transgenic mice recapitulate cardinal features of Parkinson's disease. Nat Neurosci. 2009;12:826–8. [PMC free article: PMC2845930] [PubMed: 19503083]
  • Lill CM, Roehr JT, McQueen MB, Kavvoura FK, Bagade S, Schjeide BM, Schjeide LM, Meissner E, Zauft U, Allen NC, Liu T, Schilling M, Anderson KJ, Beecham G, Berg D, Biernacka JM, Brice A, DeStefano AL, Do CB, Eriksson N, Factor SA, Farrer MJ, Foroud T, Gasser T, Hamza T, Hardy JA, Heutink P, Hill-Burns EM, Klein C, Latourelle JC, Maraganore DM, Martin ER, Martinez M, Myers RH, Nalls MA, Pankratz N, Payami H, Satake W, Scott WK, Sharma M, Singleton AB, Stefansson K, Toda T, Tung JY, Vance J, Wood NW, Zabetian CP, Young P, Tanzi RE, Khoury MJ, Zipp F, Lehrach H, Ioannidis JP, Bertram L, et al. Comprehensive research synopsis and systematic meta-analyses in Parkinson's disease genetics: The PDGene database. PLoS Genet. 2012;8:e1002548. [PMC free article: PMC3305333] [PubMed: 22438815]
  • Lu CS, Simons EJ, Wu-Chou YH, Fonzo AD, Chang HC, Chen RS, Weng YH, Rohe CF, Breedveld GJ, Hattori N, Gasser T, Oostra BA, Bonifati V. The LRRK2 I2012T, G2019S, and I2020T mutations are rare in Taiwanese patients with sporadic Parkinson's disease. Parkinsonism Relat Disord. 2005;11:521–2. [PubMed: 16256409]
  • Lu CS, Wu-Chou YH, van Doeselaar M, Simons EJ, Chang HC, Breedveld GJ, Di Fonzo A, Chen RS, Weng YH, Lai SC, Oostra BA, Bonifati V. The LRRK2 Arg1628Pro variant is a risk factor for Parkinson's disease in the Chinese population. Neurogenetics. 2008;9:271–6. [PubMed: 18716801]
  • Luzón-Toro B, Rubio de la Torre E, Delgado A, Pérez-Tur J, Hilfiker S. Mechanistic insight into the dominant mode of the Parkinson's disease-associated G2019S LRRK2 mutation. Hum Mol Genet. 2007;16:2031–9. [PubMed: 17584768]
  • MacLeod D, Dowman J, Hammond R, Leete T, Inoue K, Abeliovich A. The familial Parkinsonism gene LRRK2 regulates neurite process morphology. Neuron. 2006;52:587–93. [PubMed: 17114044]
  • Marjama-Lyons JM, Koller WC. Parkinson's disease: Update in diagnosis and symptom management. Geriatrics. 2001;56:24–5. [PubMed: 11505857]
  • Mata IF, Cosentino C, Marca V, Torres L, Mazzetti P, Ortega O, Raggio V, Aljanati R, Buzó R, Yearout D, Dieguez E, Zabetian CP. LRRK2 mutations in patients with Parkinson's disease from Peru and Uruguay. Parkinsonism Relat Disord. 2009;15:370–3. [PubMed: 18980856]
  • Mata IF, Kachergus JM, Taylor JP, Lincoln S, Aasly J, Lynch T, Hulihan MM, Cobb SA, Wu RM, Lu CS, Lahoz C, Wszolek ZK, Farrer MJ. Lrrk2 pathogenic substitutions in Parkinson's disease. Neurogenetics. 2005a;6:171–7. [PubMed: 16172858]
  • Mata IF, Ross OA, Kachergus J, Huerta C, Ribacoba R, Moris G, Blazquez M, Guisasola LM, Salvador C, Martinez C, Farrer M, Alvarez V. LRRK2 mutations are a common cause of Parkinson's disease in Spain. Eur J Neurol. 2006a;13:391–4. [PubMed: 16643318]
  • Mata IF, Taylor JP, Kachergus J, Hulihan M, Huerta C, Lahoz C, Blazquez M, Guisasola LM, Salvador C, Ribacoba R, Martinez C, Farrer M, Alvarez V. LRRK2 R1441G in Spanish patients with Parkinson's disease. Neurosci Lett. 2005b;382:309–11. [PubMed: 15925109]
  • Mata IF, Wedemeyer WJ, Farrer MJ, Taylor JP, Gallo KA. LRRK2 in Parkinson's disease: protein domains and functional insights. Trends Neurosci. 2006b;29:286–93. [PubMed: 16616379]
  • Miklossy J, Arai T, Guo JP, Klegeris A, Yu S, McGeer EG, McGeer PL. LRRK2 expression in normal and pathologic human brain and in human cell lines. J Neuropathol Exp Neurol. 2006;65:953–63. [PubMed: 17021400]
  • Mirelman A, Heman T, Yasinovsky K, Thaler A, Gurevich T, Marder K, Bressman S, Bar-Shira A, Orr-Urtreger A, Giladi N, Hausdorff JM., LRRK2 Ashkenazi Jewish Consortium. Fall risk and gait in Parkinson's disease: the role of the LRRK2 G2019S mutation. Mov Disord. 2013;28:1683–90. [PubMed: 24123150]
  • Munhoz RP, Teive HA, Francisco AN, Raskin S, Rogaeva E. Unilateral pallidotomy in a patient with parkinsonism and G2019S LRRK2 mutation. Mov Disord. 2009;24:791–2. [PubMed: 19012346]
  • Nalls MA, Plagnol V, Hernandez DG, Sharma M, Sheerin UM, Saad M, Simón-Sánchez J, Schulte C, Lesage S, Sveinbjörnsdóttir S, Stefánsson K, Martinez M, Hardy J, Heutink P, Brice A, Gasser T, Singleton AB, Wood NW. Imputation of sequence variants for identification of genetic risks for Parkinson's disease: a meta-analysis of genome-wide association studies. Lancet. 2011;377:641–9. [PMC free article: PMC3696507] [PubMed: 21292315]
  • Nandhagopal R, Mak E, Schulzer M, McKenzie J, McCormick S, Sossi V, Ruth TJ, Strongosky A, Farrer MJ, Wszolek ZK, Stoessl AJ. Progression of dopaminergic dysfunction in a LRRK2 kindred: a multitracer PET study. Neurology. 2008;71:1790–5. [PMC free article: PMC2824449] [PubMed: 19029519]
  • Nichols WC, Pankratz N, Hernandez D, Paisán-Ruíz C, Jain S, Halter CA, Michaels VE, Reed T, Rudolph A, Shults CW, Singleton A, Foroud T. Genetic screening for a single common LRRK2 mutation in familial Parkinson's disease. Lancet. 2005;365:410–2. [PubMed: 15680455]
  • Olanow CW, Stocchi F. COMT inhibitors in Parkinson's disease: can they prevent and/or reverse levodopa-induced motor complications? Neurology. 2004;62 Suppl 1:S72–81. [PubMed: 14718683]
  • Ozelius LJ, Senthil G, Saunders-Pullman R, Ohmann E, Deligtisch A, Tagliati M, Hunt AL, Klein C, Henick B, Hailpern SM, Lipton RB, Soto-Valencia J, Risch N, Bressman SB. LRRK2 G2019S as a cause of Parkinson's disease in Ashkenazi Jews. N Engl J Med. 2006;354:424–5. [PubMed: 16436782]
  • Paisán-Ruíz C, Jain S, Evans EW, Gilks WP, Simón J, van der Brug M, López de Munain A, Aparicio S, Gil AM, Khan N, Johnson J, Martinez JR, Nicholl D, Carrera IM, Pena AS, de Silva R, Lees A, Martí-Massó JF, Pérez-Tur J, Wood NW, Singleton AB. Cloning of the gene containing mutations that cause PARK8-linked Parkinson's disease. Neuron. 2004;44:595–600. [PubMed: 15541308]
  • Paisán-Ruíz C, Sáenz A, López de Munain A, Martί I, Martίnez Gil A, Martί-Massó JF, Pérez-Tur J. Familial Parkinson's disease: clinical and genetic analysis of four Basque families. Ann Neurol. 2005;57:365–72. [PubMed: 15732106]
  • Perry G, Zhu X, Babar AK, Siedlak SL, Yang Q, Ito G, Iwatsubo T, Smith MA, Chen SG. Leucine-rich repeat kinase 2 colocalizes with alpha-synuclein in Parkinson's disease, but not tau-containing deposits in tauopathies. Neurodegener Dis. 2008;5:222–4. [PMC free article: PMC2677749] [PubMed: 18322396]
  • Piccoli G, Condliffe SB, Bauer M, Giesert F, Boldt K, De Astis S, Meixner A, Sarioglu H, Vogt-Weisenhorn DM, Wurst W, Gloeckner CJ, Matteoli M, Sala C, Ueffing M. LRRK2 controls synaptic vesicle storage and mobilization within the recycling pool. J Neurosci. 2011;31:2225–37. [PubMed: 21307259]
  • Plowey ED, Cherra SJ 3rd, Liu YJ, Chu CT. Role of autophagy in G2019S-LRRK2-associated neurite shortening in differentiated SH-SY5Y cells. J Neurochem. 2008;105:1048–56. [PMC free article: PMC2361385] [PubMed: 18182054]
  • Rajput A, Dickson DW, Robinson CA, Ross OA, Dachsel JC, Lincoln SJ, Cobb SA, Rajput ML, Farrer MJ. Parkinsonism, Lrrk2 G2019S, and tau neuropathology. Neurology. 2006;67:1506–8. [PubMed: 17060589]
  • Ross OA, Spanaki C, Griffith A, Lin CH, Kachergus J, Haugarvoll K, Latsoudis H, Plaitakis A, Ferreira JJ, Sampaio C, Bonifati V, Wu RM, Zabetian CP, Farrer MJ. Haplotype analysis of Lrrk2 R1441H carriers with parkinsonism. Parkinsonism Relat Disord. 2009;15:466–7. [PMC free article: PMC2749264] [PubMed: 18952485]
  • Ross OA, Soto-Ortolaza AI, Heckman MG, Aasly JO, Abahuni N, Annesi G, Bacon JA, Bardien S, Bozi M, Brice A, Brighina L, Van Broeckhoven C, Carr J, Chartier-Harlin MC, Dardiotis E, Dickson DW, Diehl NN, Elbaz A, Ferrarese C, Ferraris A, Fiske B, Gibson JM, Gibson R, Hadjigeorgiou GM, Hattori N, Ioannidis JP, Jasinska-Myga B, Jeon BS, Kim YJ, Klein C, Kruger R, Kyratzi E, Lesage S, Lin CH, Lynch T, Maraganore DM, Mellick GD, Mutez E, Nilsson C, Opala G, Park SS, Puschmann A, Quattrone A, Sharma M, Silburn PA, Sohn YH, Stefanis L, Tadic V, Theuns J, Tomiyama H, Uitti RJ, Valente EM, van de Loo S, Vassilatis DK, Vilariño-Güell C, White LR, Wirdefeldt K, Wszolek ZK, Wu RM, Farrer MJ., Genetic Epidemiology Of Parkinson's Disease (GEO-PD) Consortium. Association of LRRK2 exonic variants with susceptibility to Parkinson's disease: a case-control study. Lancet Neurol. 2011;10:898–908. [PMC free article: PMC3208320] [PubMed: 21885347]
  • Ross OA, Toft M, Whittle AJ, Johnson JL, Papapetropoulos S, Mash DC, Litvan I, Gordon MF, Wszolek ZK, Farrer MJ, Dickson DW. Lrrk2 and Lewy body disease. Ann Neurol. 2006;59:388–93. [PubMed: 16437559]
  • Ross OA, Wu YR, Lee MC, Funayama M, Chen ML, Soto AI, Mata IF, Lee-Chen GJ, Chen CM, Tang M, Zhao Y, Hattori N, Farrer MJ, Tan EK, Wu RM. Analysis of Lrrk2 R1628P as a risk factor for Parkinson's disease. Ann Neurol. 2008;64:88–92. [PubMed: 18412265]
  • Santos-Rebouças CB, Abdalla CB, Baldi FJ, Martins PA, Corrêa JC, Gonçalves AP, Cunha MS, Borges MB, Pereira JS, Laks J, Pimentel MM. Co-occurrence of sporadic parkinsonism and late-onset Alzheimer's disease in a Brazilian male with the LRRK2 p.G2019S mutation. Genet Test. 2008;12:471–3. [PubMed: 19072560]
  • Saunders-Pullman R, Lipton RB, Senthil G, Katz M, Costan-Toth C, Derby C, Bressman S, Verghese J, Ozelius LJ. Increased frequency of the LRRK2 G2019S mutation in an elderly Ashkenazi Jewish population is not associated with dementia. Neurosci Lett. 2006;402:92–6. [PubMed: 16632201]
  • Schüpbach M, Lohmann E, Anheim M, Lesage S, Czernecki V, Yaici S, Worbe Y, Charles P, Welter ML, Pollak P, Dürr A, Agid Y, Brice A. Subthalamic nucleus stimulation is efficacious in patients with Parkinsonism and LRRK2 mutations. Mov Disord. 2007;22:119–22. [PubMed: 17080443]
  • Simón-Sánchez J, Martí-Massó JF, Sánchez-Mut JV, Paisán-Ruíz C, Martínez-Gil A, Ruiz-Martínez J, Sáenz A, Singleton AB, López de Munain A, Pérez-Tur J. Parkinson's disease due to the R1441G mutation in Dardarin: a founder effect in the Basques. Mov Disord. 2006;21:1954–9. [PubMed: 16991141]
  • Smith WW, Pei Z, Jiang H, Dawson VL, Dawson TM, Ross CA. Kinase activity of mutant LRRK2 mediates neuronal toxicity. Nat Neurosci. 2006;9:1231–3. [PubMed: 16980962]
  • Smith WW, Pei Z, Jiang H, Moore DJ, Liang Y, West AB, Dawson VL, Dawson TM, Ross CA. Leucine-rich repeat kinase 2 (LRRK2) interacts with parkin, and mutant LRRK2 induces neuronal degeneration. Proc Natl Acad Sci U S A. 2005;102:18676–81. [PMC free article: PMC1317945] [PubMed: 16352719]
  • Tan EK, Peng R, Teo YY, Tan LC, Angeles D, Ho P, Chen ML, Lin CH, Mao XY, Chang XL, Prakash KM, Liu JJ, Au WL, Le WD, Jankovic J, Burgunder JM, Zhao Y, Wu RM. Multiple LRRK2 variants modulate risk of Parkinson disease: a Chinese multicenter study. Hum Mutat. 2010;31:561–8. [PubMed: 20186690]
  • Tan EK, Tan LC, Lim HQ, Li R, Tang M, Yih Y, Pavanni R, Prakash KM, Fook-Chong S, Zhao Y. LRRK2 R1628P increases risk of Parkinson's disease: replication evidence. Hum Genet. 2008;124:287–8. [PubMed: 18781329]
  • Tan EK, Zhao Y, Skipper L, Tan MG, Di Fonzo A, Sun L, Fook-Chong S, Tang S, Chua E, Yuen Y, Tan L, Pavanni R, Wong MC, Kolatkar P, Lu CS, Bonifati V, Liu JJ. The LRRK2 Gly2385Arg variant is associated with Parkinson's disease: genetic and functional evidence. Hum Genet. 2007;120:857–63. [PubMed: 17019612]
  • Taylor JP, Mata IF, Farrer MJ. LRRK2: a common pathway for parkinsonism, pathogenesis and prevention? Trends Mol Med. 2006;12:76–82. [PubMed: 16406842]
  • Toft M, Mata IF, Kachergus JM, Ross OA, Farrer MJ. LRRK2 mutations and Parkinsonism. Lancet. 2005;365:1229–30. [PubMed: 15811454]
  • Tomiyama H, Li Y, Funayama M, Hasegawa K, Yoshino H, Kubo S, Sato K, Hattori T, Lu CS, Inzelberg R, Djaldetti R, Melamed E, Amouri R, Gouider-Khouja N, Hentati F, Hatano Y, Wang M, Imamichi Y, Mizoguchi K, Miyajima H, Obata F, Toda T, Farrer MJ, Mizuno Y, Hattori N. Clinicogenetic study of mutations in LRRK2 exon 41 in Parkinson's disease patients from 18 countries. Mov Disord. 2006;21:1102–8. [PubMed: 16622854]
  • Tong Y, Giaime E, Yamaguchi H, Ichimura T, Liu Y, Si H, Cai H, Bonventre JV, Shen J. Loss of leucine-rich repeat kinase 2 causes age-dependent bi-phasic alterations of the autophagy pathway. Mol Neurodegener. 2012;7:2. [PMC free article: PMC3296570] [PubMed: 22230652]
  • Trinh J, Amouri R, Duda JE, Morley JF, Read M, Donald A, Vilarino-Guell C, Thompson C, Szu Tu C, Gustavsson EK, Sassi SB, Hentati E, Zouari M, Farhat E, Nabli F, Hentati F, Farrer MJ. A comparative study of Parkinson’s disease and leucine-rich repeat kinase 2 p.G2019S parkinsonism. Neurobiol Aging. 2014a;35:1125–31. [PubMed: 24355527]
  • Trinh J, Guella I, Farrer M. Disease penetrance of late-onset parkinsonism: a meta-analysis. JAMA Neurol. 2014b;71:1535–9. [PubMed: 25330418]
  • Ujiie S, Hatano T, Kubo S, Imai S, Sato S, Uchihara T, Yagishita S, Hasegawa K, Kowa H, Sakai F, Hattori N. LRRK2 I2020T mutation is associated with tau pathology. Parkinsonism Relat Disord. 2012;18:819–23. [PubMed: 22525366]
  • van Egmond WN, Kortholt A, Plak K, Bosgraaf L, Bosgraaf S, Keizer-Gunnink I, van Haastert PJ. Intramolecular Activation Mechanism of the Dictyostelium LRRK2 Homolog Roco Protein GbpC. J Biol Chem. 2008;283:30412–20. [PMC free article: PMC2662088] [PubMed: 18703517]
  • West AB, Moore DJ, Biskup S, Bugayenko A, Smith WW, Ross CA, Dawson VL, Dawson TM. Parkinson's disease-associated mutations in leucine-rich repeat kinase 2 augment kinase activity. Proc Natl Acad Sci U S A. 2005;102:16842–7. [PMC free article: PMC1283829] [PubMed: 16269541]
  • Williams-Gray CH, Goris A, Foltynie T, Brown J, Maranian M, Walton A, Compston DA, Sawcer SJ, Barker RA. Prevalence of the LRRK2 G2019S mutation in a UK community based idiopathic Parkinson's disease cohort. J Neurol Neurosurg Psychiatry. 2006;77:665–7. [PMC free article: PMC2117467] [PubMed: 16614029]
  • Wszolek ZK, Pfeiffer RF, Tsuboi Y, Uitti RJ, McComb RD, Stoessl AJ, Strongosky AJ, Zimprich A, Muller-Myhsok B, Farrer MJ, Gasser T, Calne DB, Dickson DW. Autosomal dominant parkinsonism associated with variable synuclein and tau pathology. Neurology. 2004;62:1619–22. [PubMed: 15136696]
  • Zabetian CP, Morino H, Ujike H, Yamamoto M, Oda M, Maruyama H, Izumi Y, Kaji R, Griffith A, Leis BC, Roberts JW, Yearout D, Samii A, Kawakami H. Identification and haplotype analysis of LRRK2 G2019S in Japanese patients with Parkinson disease. Neurology. 2006;67:697–9. [PubMed: 16728648]
  • Zimprich A, Biskup S, Leitner P, Lichtner P, Farrer M, Lincoln S, Kachergus J, Hulihan M, Uitti RJ, Calne DB, Stoessl AJ, Pfeiffer RF, Patenge N, Carbajal IC, Vieregge P, Asmus F, Muller-Myhsok B, Dickson DW, Meitinger T, Strom TM, Wszolek ZK, Gasser T. Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology. Neuron. 2004;44:601–7. [PubMed: 15541309]

Chapter Notes

Author Notes

Dr Ross currently directs the Division of the Neurogenetics at Mayo Clinic Jacksonville, and the Genetic Core of a Morris K Udall Center of Excellence for the Genetics of Parkinson's disease. Current research is supported through the National Institutes of Health (NINDS), the Michael J Fox Foundation, and the Mayo Foundation.

Dr Farrer and colleagues' research interests are focused on the genetic analysis of parkinsonism and related movement and memory disorders. Research interests include statistical and molecular genetics, functional genomics, and applied neurobiology, including the creation of animal models of parkinsonism based on molecular etiology. Dr Farrer reports (a) International Publication Number WO 2006/045392 A2; (b) International Publication Number WO 2006/068492 A1; (c) US Patent Number 7,544,786; and (d) Norwegian patent 323175, related to LRRK2. Dr Farrer reports salary and royalty payment from the Pharmaceutical Industry for sponsored research on Lrrk2 biology and mouse model characterization. As of August 2008, Mayo and Dr Farrer have received royalties from the licensing of these technologies of greater than $10,000, the US federal threshold for significant financial interest.


  • Morris K Udall Center of Excellence for the Genetics of Parkinson's disease
  • Current research supported through the National Institutes of Health (NINDS, NIEHS and NIA), the Michael J Fox Foundation, and the Mayo Foundation
  • All the individuals involved in our research including the many scientists, clinicians, and especially the patients and their families

Author History

Matthew Farrer, PhD (2006-present)
Ilaria Guella, PhD (2014-present)
Owen A Ross, PhD (2006-present)
Jeremy T Stone, BSc; Mayo Clinic (2006-2010)
Joanne Trinh, BSc (2014-present)

Revision History

  • 11 December 2014 (me) Comprehensive update posted live
  • 13 September 2012 (me) Comprehensive update posted live
  • 29 April 2010 (me) Comprehensive update posted live
  • 2 November 2006 (me) Review posted to live Web site
  • 6 July 2006 (mf) Original submission
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