Sardi S Pablo, Cheng Seng H, Shihabuddin Lamya S
Genzyme, a Sanofi Company, 49 New York Avenue, Framingham, MA 01701, USA.
Genzyme, a Sanofi Company, 49 New York Avenue, Framingham, MA 01701, USA.
Prog Neurobiol. 2015 Feb;125:47-62. doi: 10.1016/j.pneurobio.2014.12.001. Epub 2015 Jan 6.
Gaucher disease, the most common lysosomal storage disease, is caused by a recessively inherited deficiency in glucocerebrosidase and subsequent accumulation of toxic lipid substrates. Heterozygous mutations in the lysosomal glucocerebrosidase gene (GBA1) have recently been recognized as the highest genetic risk factor for the development of α-synuclein aggregation disorders ("synucleinopathies"), including Parkinson's disease (PD) and dementia with Lewy bodies (DLB). Despite the wealth of experimental, clinical and genetic evidence that supports the association between mutant genotypes and synucleinopathy risk, the precise mechanisms by which GBA1 mutations lead to PD and DLB remain unclear. Decreased glucocerebrosidase activity has been demonstrated to promote α-synuclein misprocessing. Furthermore, aberrant α-synuclein species have been reported to downregulate glucocerebrosidase activity, which further contributes to disease progression. In this review, we summarize the recent findings that highlight the complexity of this pathogenetic link and how several pathways that connect glucocerebrosidase insufficiency with α-synuclein misprocessing have emerged as potential therapeutic targets. From a translational perspective, we discuss how various therapeutic approaches to lysosomal dysfunction have been explored for the treatment of GBA1-related synucleinopathies, and potentially, for non-GBA1-associated neurodegenerative diseases. In summary, the link between GBA1 and synucleinopathies has become the paradigm of how the study of a rare lysosomal disease can transform the understanding of the etiopathology, and hopefully the treatment, of a more prevalent and multifactorial disorder.
戈谢病是最常见的溶酶体贮积病，由葡萄糖脑苷脂酶隐性遗传缺陷及随后有毒脂质底物的蓄积所致。溶酶体葡萄糖脑苷脂酶基因（GBA1）的杂合突变最近被认为是α-突触核蛋白聚集性疾病（“突触核蛋白病”）发生的最高遗传风险因素，这些疾病包括帕金森病（PD）和路易体痴呆（DLB）。尽管有大量实验、临床和遗传学证据支持突变基因型与突触核蛋白病风险之间的关联，但GBA1突变导致PD和DLB的确切机制仍不清楚。已证明葡萄糖脑苷脂酶活性降低会促进α-突触核蛋白的错误加工。此外，据报道异常的α-突触核蛋白会下调葡萄糖脑苷脂酶活性，这进一步促进了疾病进展。在本综述中，我们总结了最近的研究发现，这些发现突出了这种致病联系的复杂性，以及将葡萄糖脑苷脂酶不足与α-突触核蛋白错误加工联系起来的几种途径如何成为潜在的治疗靶点。从转化医学的角度，我们讨论了如何探索各种治疗溶酶体功能障碍的方法来治疗与GBA1相关的突触核蛋白病，并有可能用于治疗非GBA1相关的神经退行性疾病。总之，GBA1与突触核蛋白病之间的联系已成为一个范例，即对一种罕见的溶酶体疾病的研究如何能够改变对一种更常见且多因素疾病的病因病理学的理解，并有望改变其治疗方法。
