Unit of Transgenesis, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA.
Neuron. 2009 Dec 24;64(6):807-27. doi: 10.1016/j.neuron.2009.11.006.
Mutations in alpha-synuclein and Leucine-rich repeat kinase 2 (LRRK2) are linked to autosomal dominant forms of Parkinson's disease (PD). However, little is known about any potential pathophysiological interplay between these two PD-related genes. Here we show in transgenic mice that although overexpression of LRRK2 alone did not cause neurodegeneration, the presence of excess LRRK2 greatly accelerated the progression of neuropathological abnormalities developed in PD-related A53T alpha-synuclein transgenic mice. Moreover, we found that LRRK2 promoted the abnormal aggregation and somatic accumulation of alpha-synuclein in A53T mice, which likely resulted from the impairment of microtubule dynamics, Golgi organization, and the ubiquitin-proteasome pathway. Conversely, genetic ablation of LRRK2 preserved the Golgi structure and suppressed the aggregation and somatic accumulation of alpha-synuclein, and thereby delayed the progression of neuropathology in A53T mice. These findings demonstrate that overexpression of LRRK2 enhances alpha-synuclein-mediated cytotoxicity and suggest inhibition of LRRK2 expression as a potential therapeutic option for ameliorating alpha-synuclein-induced neurodegeneration.
α-突触核蛋白和富亮氨酸重复激酶 2（LRRK2）的突变与常染色体显性形式的帕金森病（PD）有关。然而，人们对这两个与 PD 相关的基因之间任何潜在的病理生理学相互作用知之甚少。在这里，我们在转基因小鼠中表明，尽管单独过表达 LRRK2本身不会导致神经退行性变，但过量的 LRRK2 大大加速了 PD 相关 A53T α-突触核蛋白转基因小鼠中发展的神经病理学异常的进展。此外，我们发现 LRRK2 促进了 A53T 小鼠中 α-突触核蛋白的异常聚集和体细胞积累，这可能是由于微管动力学、高尔基组织和泛素-蛋白酶体途径受损所致。相反，LRRK2 的基因缺失保留了高尔基结构，抑制了 α-突触核蛋白的聚集和体细胞积累，从而延缓了 A53T 小鼠神经病理学的进展。这些发现表明，LRRK2 的过表达增强了 α-突触核蛋白介导的细胞毒性，并表明抑制 LRRK2 的表达可能是改善 α-突触核蛋白诱导的神经退行性变的潜在治疗选择。
