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Neurology. 2010 Nov 30;75(22):2017-20. doi: 10.1212/WNL.0b013e3181ff9685.

Mitochondrial impairment in patients with Parkinson disease with the G2019S mutation in LRRK2.

Author information

1
Academic Neurology Unit, Medical School, University of Sheffield, Beech Hill Road, Sheffield S10 2RX, UK.

Abstract

OBJECTIVE:

The LRRK2(G2019S) mutation is the most common identifiable cause for Parkinson disease (PD), but the underlying mechanisms leading to neuronal cell death remain largely unclear. Impaired mitochondrial function and morphology have been described in different in vivo and in vitro model systems of early-onset PD (EOPD) as well as in EOPD patient tissue. The aim of our study was to assess mitochondrial function and morphology in LRRK2(G2019S) mutant patient tissue to determine whether impaired mitochondrial function and morphology are shared features in early-onset and late-onset PD.

METHODS:

Skin biopsies were taken from 5 patients with PD with the LRRK2(G2019S) mutation. Assessment of mitochondrial membrane potential and intracellular ATP levels as well as substrate-linked mitochondrial ATP production assays were all carried out on 3 independent cell preparations per patient. Results were compared to 5 age-matched controls. Mitochondrial elongation and interconnectivity was assessed using previously published methods.

RESULTS:

Both mitochondrial membrane potential and total intracellular ATP levels were decreased in the G2019S mutation carriers. Subsequently undertaken mitochondrial ATP production assays suggested that the observed reduction is at least partially due to impaired mitochondrial function. Mitochondrial elongation and interconnectivity were increased in the LRRK2(G2019S) patient cohort.

CONCLUSION:

Our results provide evidence for impaired mitochondrial function and morphology in LRRK2(G2019S) mutant patient tissue. Further studies are required to determine whether the impaired mitochondrial function is due to increased LRRK2 kinase activity or other mechanisms such as LRRK2 haploinsufficiency.

PMID:
21115957
DOI:
10.1212/WNL.0b013e3181ff9685
[Indexed for MEDLINE]

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