Department of Biomedical Sciences, Neuroscience Research Institute, and Department of Medicine, Seoul National University College of Medicine, Seoul, Korea.
Department of Neurology, Juntendo University, School of Medicine, Tokyo 113-8421, Japan.
Brain. 2019 Sep 1;142(9):2845-2859. doi: 10.1093/brain/awz205.
Mutations in lysosomal genes increase the risk of neurodegenerative diseases, as is the case for Parkinson's disease. Here, we found that pathogenic and protective mutations in arylsulfatase A (ARSA), a gene responsible for metachromatic leukodystrophy, a lysosomal storage disorder, are linked to Parkinson's disease. Plasma ARSA protein levels were changed in Parkinson's disease patients. ARSA deficiency caused increases in α-synuclein aggregation and secretion, and increases in α-synuclein propagation in cells and nematodes. Despite being a lysosomal protein, ARSA directly interacts with α-synuclein in the cytosol. The interaction was more extensive with protective ARSA variant and less with pathogenic ARSA variant than wild-type. ARSA inhibited the in vitro fibrillation of α-synuclein in a dose-dependent manner. Ectopic expression of ARSA reversed the α-synuclein phenotypes in both cell and fly models of synucleinopathy, the effects correlating with the extent of the physical interaction between these molecules. Collectively, these results suggest that ARSA is a genetic modifier of Parkinson's disease pathogenesis, acting as a molecular chaperone for α-synuclein.
溶酶体基因的突变会增加神经退行性疾病的风险，帕金森病就是一个例子。在这里，我们发现导致黏脂贮积症（一种溶酶体贮积病）的芳基硫酸酯酶 A (ARSA)基因的致病性和保护性突变与帕金森病有关。帕金森病患者的血浆 ARSA 蛋白水平发生了变化。ARSA 缺乏会导致α-突触核蛋白聚集和分泌增加，并导致细胞和线虫中α-突触核蛋白的传播增加。尽管 ARSA 是一种溶酶体蛋白，但它在细胞质中与α-突触核蛋白直接相互作用。与野生型相比，这种相互作用在保护性 ARSA 变体中更为广泛，而在致病性 ARSA 变体中则较少。ARSA 以剂量依赖的方式抑制α-突触核蛋白的体外纤维形成。ARSA 的异位表达在α-突触核蛋白病的细胞和果蝇模型中逆转了α-突触核蛋白表型，这些效果与这些分子之间的物理相互作用的程度相关。总之，这些结果表明 ARSA 是帕金森病发病机制的遗传修饰因子，作为α-突触核蛋白的分子伴侣发挥作用。
