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

    Research output: Contribution to journalArticle

    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 1 2014

    ASJC Scopus subject areas

    • Neuroscience(all)

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  • Cite this

    Parisiadou, L., Yu, J., Sgobio, C., Xie, C., Liu, G., Sun, L., Gu, X. L., Lin, X., Crowley, N. A., Lovinger, D. M., & Cai, H. (2014). LRRK2 regulates synaptogenesis and dopamine receptor activation through modulation of PKA activity. Nature neuroscience, 17(3), 367-376. https://doi.org/10.1038/nn.3636