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LRRK2 regulates synaptogenesis and dopamine receptor activation through modulation of PKA activity.
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Nat Neurosci 2014 Mar; 17(3):367-76
Authors: 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
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 II? (PKARII?). 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 PKARII? 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 [PubMed - as supplied by publisher]