1] Transgenics Section, Laboratory of Neurogenetics, National Institute on Aging, US National Institutes of Health, Bethesda, Maryland, USA. [2] Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA. [3].
1] Transgenics Section, Laboratory of Neurogenetics, National Institute on Aging, US National Institutes of Health, Bethesda, Maryland, USA. [2] Department of Geriatrics, Beijing Geriatric Hospital, Beijing, China. [3].
Nat Neurosci. 2014 Mar;17(3):367-76. doi: 10.1038/nn.3636. Epub 2014 Jan 26.
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.
富含亮氨酸重复激酶 2（LRRK2）在纹状体投射神经元（SPNs）中富集。我们发现，LRRK2 在突触发生过程中和多巴胺受体 Drd1 激活时，负调控 SPN 中的蛋白激酶 A（PKA）活性。LRRK2 与 PKA 调节亚基 IIβ（PKARIIβ）相互作用。LRRK2 的缺失促进了 PKA 的突触易位，并增加了 PKA 介导的肌动蛋白解聚酶原丝氨酸磷酸化和谷氨酸受体 GluR1 的磷酸化，导致发育中的 SPN 异常突触发生和传递。此外，在年轻和年老的 Lrrk2(-/-) 小鼠用 Drd1 激动剂处理后，PKA 依赖性的 GluR1 磷酸化也在纹状体中异常增强。值得注意的是，一种与帕金森病相关的 Lrrk2 R1441C 错义突变，破坏了 LRRK2 与 PKARIIβ 的相互作用，也导致了 SPN 中 PKA 活性的过度增加。我们的研究结果揭示了 LRRK2 在 PKA 信号中的一个以前未知的调节作用，并提示了帕金森病中 SPN 功能障碍的一种发病机制。
