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

Loukia Parisiadou*, Jia Yu, Carmelo Sgobio, Chengsong Xie, Guoxiang Liu, Lixin Sun, Xing Long Gu, Xian Lin, Nicole A. Crowley, David M. Lovinger, Huaibin Cai

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

110 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)367-376
Number of pages10
JournalNature neuroscience
Volume17
Issue number3
DOIs
StatePublished - Mar 2014

ASJC Scopus subject areas

  • Neuroscience(all)

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