Other
11 Authors
- Gu XL,
- Lovinger DM,
- Cai H,
- Crowley NA,
- Parisiadou L,
- Liu G,
- Sun L,
- Lin X,
- Yu J,
- Xie C,
- Sgobio C
| First Author | Parisiadou L | Year | 2014 |
| Journal | Nat Neurosci | Volume | 17 |
| Issue | 3 | Pages | 367-76 |
| PubMed ID | 24464040 | Mgi Jnum | J:206832 |
| Mgi Id | MGI:5553024 | Doi | 10.1038/nn.3636 |
| Citation | Parisiadou L, et al. (2014) LRRK2 regulates synaptogenesis and dopamine receptor activation through modulation of PKA activity. Nat Neurosci 17(3):367-76 |
| abstractText | 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 IIbeta (PKARIIbeta). 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 PKARIIbeta 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. |
