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Nat Neurosci. 2014 Mar;17(3):367-76. doi: 10.1038/nn.3636. Epub 2014 Jan 26.

LRRK2 regulates synaptogenesis and dopamine receptor activation through modulation of PKA activity.

Author information

1
1] Transgenics Section, Laboratory of Neurogenetics, National Institute on Aging, US National Institutes of Health, Bethesda, Maryland, USA. [2] Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA. [3].
2
1] Transgenics Section, Laboratory of Neurogenetics, National Institute on Aging, US National Institutes of Health, Bethesda, Maryland, USA. [2] Department of Geriatrics, Beijing Geriatric Hospital, Beijing, China. [3].
3
1] Transgenics Section, Laboratory of Neurogenetics, National Institute on Aging, US National Institutes of Health, Bethesda, Maryland, USA. [2].
4
Transgenics Section, Laboratory of Neurogenetics, National Institute on Aging, US National Institutes of Health, Bethesda, Maryland, USA.
5
1] Transgenics Section, Laboratory of Neurogenetics, National Institute on Aging, US National Institutes of Health, Bethesda, Maryland, USA. [2] Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.
6
Laboratory of Integrative Neuroscience, National Institute on Alcohol Abuse and Alcoholism, US National Institutes of Health, Rockville, Maryland, USA.

Erratum in

  • Nat Neurosci. 2014 Sep;17(9):1287.

Abstract

Leucine-rich repeat kinase 2 (LRRK2) is enriched in the striatal projection neurons (SPNs). We found that LRRK2 negatively regulates protein kinase A (PKA) activity in the SPNs during synaptogenesis and in response to dopamine receptor Drd1 activation. LRRK2 interacted with PKA regulatory subunit IIβ (PKARIIβ). A lack of LRRK2 promoted the synaptic translocation of PKA and increased PKA-mediated phosphorylation of actin-disassembling enzyme cofilin and glutamate receptor GluR1, resulting in abnormal synaptogenesis and transmission in the developing SPNs. Furthermore, PKA-dependent phosphorylation of GluR1 was also aberrantly enhanced in the striatum of young and aged Lrrk2(-/-) mice after treatment with a Drd1 agonist. Notably, a Parkinson's disease-related Lrrk2 R1441C missense mutation that impaired the interaction of LRRK2 with PKARIIβ also induced excessive PKA activity in the SPNs. Our findings reveal a previously unknown regulatory role for LRRK2 in PKA signaling and suggest a pathogenic mechanism of SPN dysfunction in Parkinson's disease.

PMID:
24464040
PMCID:
PMC3989289
DOI:
10.1038/nn.3636
[Indexed for MEDLINE]
Free PMC Article

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