Arylsulfatase A, a genetic modifier of Parkinson's disease, is an α-synuclein chaperone
Arylsulfatase A, a genetic modifier of Parkinson's disease, is an α-synuclein chaperone
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芳基硫酸酯酶A是一种α-突触核蛋白伴侣，是帕金森病的遗传修饰剂
DOI：
10.1093/brain/awz205
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发表时间：
2019-09-01
期刊：
影响因子：
14.5
通讯作者：
Lee, Seung-Jae
中科院分区：
文献类型：
--
作者：
Lee, Jun Sung;Kanai, Kazuaki;Lee, Seung-Jae
溶酶体基因突变会增加神经退行性疾病的风险，例如帕金森病。在这里，我们发现芳基硫酸酯酶 A (ARSA) 的致病性和保护性突变与帕金森病有关，芳基硫酸酯酶 A (ARSA) 是一种导致异染性脑白质营养不良（一种溶酶体贮积症）的基因。帕金森病患者血浆 ARSA 蛋白水平发生变化。 ARSA 缺陷导致 α-突触核蛋白聚集和分泌增加，以及细胞和线虫中 α-突触核蛋白繁殖增加。尽管是溶酶体蛋白，ARSA 仍直接与细胞质中的 α-突触核蛋白相互作用。与野生型相比，保护性 ARSA 变体的相互作用更广泛，而致病性 ARSA 变体的相互作用更小。 ARSA 以剂量依赖性方式抑制 α-突触核蛋白的体外纤维颤动。 ARSA 的异位表达逆转了突触核蛋白病细胞和果蝇模型中的 α-突触核蛋白表型，其效应与这些分子之间的物理相互作用的程度相关。总的来说，这些结果表明 ARSA 是帕金森病发病机制的遗传修饰剂，充当 α-突触核蛋白的分子伴侣。
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 alpha-synuclein aggregation and secretion, and increases in alpha-synuclein propagation in cells and nematodes. Despite being a lysosomal protein, ARSA directly interacts with alpha-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 alpha-synuclein in a dose-dependent manner. Ectopic expression of ARSA reversed the alpha-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 alpha-synuclein.