Department of Neurology, Brigham and Women's Hospital, Boston, United States.
Program in Neuroscience, Harvard Medical School, Boston, United States.
Elife. 2024 Jun 10;12:RP92673. doi: 10.7554/eLife.92673.
Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common genetic cause of Parkinson's disease (PD). However, whether LRRK2 mutations cause PD and degeneration of dopaminergic (DA) neurons via a toxic gain-of-function or a loss-of-function mechanism is unresolved and has pivotal implications for LRRK2-based PD therapies. In this study, we investigate whether and its functional homolog play a cell-intrinsic role in DA neuron survival through the development of DA neuron-specific conditional double knockout (cDKO) mice. Unlike germline DKO mice, DA neuron-restricted cDKO mice exhibit normal mortality but develop age-dependent loss of DA neurons, as shown by the progressive reduction of DA neurons in the substantia nigra pars compacta (SNpc) at the ages of 20 and 24 months. Moreover, DA neurodegeneration is accompanied with increases in apoptosis and elevated microgliosis in the SNpc as well as decreases in DA terminals in the striatum, and is preceded by impaired motor coordination. Taken together, these findings provide the unequivocal evidence for the cell-intrinsic requirement of LRRK in DA neurons and raise the possibility that LRRK2 mutations may impair its protection of DA neurons, leading to DA neurodegeneration in PD.
富含亮氨酸重复激酶 2 (LRRK2) 突变是帕金森病 (PD) 最常见的遗传原因。然而，LRRK2 突变是否通过毒性获得性功能或功能丧失机制导致 PD 和多巴胺能 (DA) 神经元变性仍未解决，这对基于 LRRK2 的 PD 治疗具有重要意义。在这项研究中，我们通过开发 DA 神经元特异性 LRRK2 条件性双敲除 (cDKO) 小鼠，研究 是否及其功能同源物 在 DA 神经元存活中发挥细胞内固有作用。与 种系 DKO 小鼠不同，DA 神经元限制性 cDKO 小鼠表现出正常的死亡率，但随着年龄的增长会出现 DA 神经元的逐渐丧失，这表现为在 20 个月和 24 个月时黑质致密部 (SNpc) 中的 DA 神经元逐渐减少。此外，DA 神经退行性变伴随着 SNpc 中细胞凋亡和小胶质细胞增生的增加，以及纹状体中 DA 末梢的减少，并且伴随着运动协调能力受损。总之，这些发现为 LRRK 在 DA 神经元中的细胞内固有要求提供了明确的证据，并提出了 LRRK2 突变可能损害其对 DA 神经元的保护作用，从而导致 PD 中 DA 神经退行性变的可能性。
