Parkinson’s disease (PD), the second most common neurodegenerative disorder after Alzheimer’s disease, is a clinically heterogeneous disorder, with obscure etiology and no disease-modifying therapy to date. Currently, there is no available biomarker for PD endophenotypes or disease progression. Accumulating evidence suggests that mutations in genes related to lysosomal function or lysosomal storage disorders may affect the risk of PD development, such as GBA1 gene mutations. In this context, recent studies have revealed the emerging role of arylsulfatase A (ASA), a lysosomal hydrolase encoded by the ARSA gene causing metachromatic leukodystrophy (MLD) in PD pathogenesis. In particular, altered ASA levels have been detected during disease progression, and reduced enzymatic activity of ASA has been associated with an atypical PD clinical phenotype, including early cognitive impairment and essential-like tremor. Clinical evidence further reveals that specific ARSA gene variants may act as genetic modifiers in PD. Recent in vitro and in vivo studies indicate that ASA may function as a molecular chaperone interacting with α-synuclein (SNCA) in the cytoplasm, preventing its aggregation, secretion and cell-to-cell propagation. In this review, we summarize the results of recent preclinical and clinical studies on the role of ASA in PD, aiming to shed more light on the potential implication of ASA in PD pathogenesis and highlight its biomarker potential.

中文翻译：

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帕金森氏病中的芳基硫酸酯酶A（ASA）：从发病机理到生物标志物的潜力

帕金森氏病（PD）是继阿尔茨海默氏病之后第二大最常见的神经退行性疾病，是一种临床上的异质性疾病，病因不明，迄今尚无可改善疾病的疗法。当前，没有可用于PD内表型或疾病进展的生物标记。越来越多的证据表明，与溶酶体功能或溶酶体贮积病相关的基因突变可能会影响PD发生的风险，例如GBA1基因突变。在这种情况下，最近的研究表明，芳基硫酸酯酶A（ASA）的新兴作用是由ARSA编码的溶酶体水解酶基因导致PD发病机制中的变色性白细胞营养不良（MLD）。特别是，在疾病进展过程中已检测到ASA水平发生了变化，ASA的酶活性降低已与非典型的PD临床表型相关，包括早期认知障碍和本质性震颤。临床证据进一步揭示了特定的ARSA基因变体可以作为PD中的遗传修饰物。最近的体外和体内研究表明，ASA可能充当与细胞质中的α-突触核蛋白（SNCA）相互作用的分子伴侣，从而阻止其聚集，分泌和细胞间繁殖。在这篇综述中，我们总结了有关ASA在PD中的作用的最新临床前和临床研究结果，旨在更多地了解ASA在PD发病机理中的潜在影响，并突出其生物标志物的潜力。