Sandhoff disease (SD) is a lysosomal storage disease, caused by loss of β-hexosaminidase (HEX) activity resulting in the accumulation of ganglioside GM2. There are shared features between SD and Parkinson’s disease (PD). α-synuclein (aSYN) inclusions, the diagnostic hallmark sign of PD, are frequently found in the brain in SD patients and HEX knockout mice, and HEX activity is reduced in the substantia nigra in PD. In this study, we biochemically demonstrate that HEX deficiency in mice causes formation of high-molecular weight (HMW) aSYN and ubiquitin in the brain. As expected from HEX enzymatic function requirements, overexpression in vivo of HEXA and B combined, but not either of the subunits expressed alone, increased HEX activity as evidenced by histochemical assays. Biochemically, such HEX gene expression resulted in increased conversion of GM2 to its breakdown product GM3. In a neurodegenerative model of overexpression of aSYN in rats, increasing HEX activity by AAV6 gene transfer in the substantia nigra reduced aSYN embedding in lipid compartments and rescued dopaminergic neurons from degeneration. Overall, these data are consistent with a paradigm shift where lipid abnormalities are central to or preceding protein changes typically associated with PD.

中文翻译：

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上调啮齿动物中的 β-己糖胺酶活性可防止 α-突触核蛋白脂质关联，并保护多巴胺能神经元免受 α-突触核蛋白介导的神经毒性。


桑德霍夫病 (SD) 是一种溶酶体贮积病，由 β-己糖胺酶 (HEX) 活性丧失导致神经节苷脂 GM2 积累引起。 SD 和帕金森病 (PD) 之间有一些共同特征。 α-突触核蛋白 (aSYN) 内含物是 PD 的诊断标志，经常在 SD 患者和 HEX 敲除小鼠的大脑中发现，并且 PD 黑质中的 HEX 活性降低。在这项研究中，我们通过生化方法证明小鼠 HEX 缺陷会导致大脑中高分子量 (HMW) aSYN 和泛素的形成。正如根据 HEX 酶功能要求所预期的那样，HEXA 和 B 组合的体内过表达（而不是任一亚基单独表达）增加了 HEX 活性，如组织化学测定所证明的。从生物化学角度来看，这种 HEX 基因表达导致 GM2 向其分解产物 GM3 的转化增加。在大鼠 aSYN 过度表达的神经退行性模型中，通过黑质中的 AAV6 基因转移增加 HEX 活性，减少了 aSYN 在脂质区室中的嵌入，并挽救多巴胺能神经元免于退化。总体而言，这些数据与范式转变一致，其中脂质异常是通常与 PD 相关的蛋白质变化的核心或先于蛋白质变化。