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

Leucine-rich repeat kinase 2 (LRRK2) is enriched in the striatal projection neurons (SPNs). We found that LRRK2 negatively regulates protein kinase A activity in the SPNs during synaptogenesis and in response to dopamine receptor Drd1 activation. LRRK2 interacted with regulatory subunit IIβ A lack of LRRK2 promoted the synaptic translocation of duanyu1529 and increased phosphorylation of actin-disassembling enzyme cofilin and glutamate receptor GluR1, resulting in abnormal synaptogenesis and transmission in the developing SPNs. Furthermore, 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 also induced excessive duanyu1529 activity in the SPNs. Our findings reveal a previously unknown regulatory role for LRRK2 in duanyu1529 signaling and suggest a pathogenic mechanism of SPN dysfunction in Parkinson's disease.

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