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

The authors show that leucine-rich repeat kinase 2 (Lrrk2) binds protein kinase A (PKA) regulatory subunit IIβ to decrease PKA activity in striatal projection neurons (SPNs). Lrrk2 regulation of PKA prevents its synaptic translocation, altering synaptogenesis and transmission in developing SPNs. A Parkinson's disease–associated mutant of Lrrk2 prevented its interaction with PKARIIβ. 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.