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Abstract：
The spinocerebellar ataxias (SCA) comprise a group of inherited neurodegenerative diseases. Machado-Joseph Disease (MJD) or spinocerebellar ataxia 3 (SCA3) is the most common autosomal dominant form, caused by the expansion of CAG repeats within the ataxin-3 (ATXN3) gene. This mutation results in the expression of an abnormal protein containing long polyglutamine (polyQ) stretches that confers a toxic gain of function and leads to misfolding and aggregation of ATXN3 in neurons. As a result of the neurodegenerative process, SCA3 patients are severely disabled and die prematurely. Several screening approaches, e.g., druggable genome-wide and drug library screenings have been performed, focussing on the reduction in stably overexpressed ATXN3(polyQ) protein and improvement in the resultant toxicity. Transgenic overexpression models of toxic ATXN3, however, missed potential modulators of endogenous ATXN3 regulation. In another approach to identify modifiers of endogenous ATXN3 expression using a CRISPR/Cas9-modified SK-N-SH wild-type cell line with a GFP-T2A-luciferase (LUC) cassette under the control of the endogenous ATXN3 promotor, four statins were identified as potential activators of expression. We here provide an overview of the high throughput screening approaches yet performed to find compounds or genomic modifiers of ATXN3(polyQ) toxicity in different SCA3 model organisms and cell lines to ameliorate and halt SCA3 progression in patients. Furthermore, the putative role of cholesterol in neurodegenerative diseases (NDDs) in general and SCA3 in particular is discussed.
摘要：
脊髓小脑共济失调(SCA)包括一组遗传性神经退行性疾病。Machado-Joseph病（MJD）或脊髓小脑共济失调3（SCA3）是最常见的常染色体显性形式，由ataxin-3（ATXN3）基因内CAG重复序列的扩展引起。该突变导致含有长的聚谷氨酰胺(polyQ)延伸的异常蛋白质的表达,所述长的聚谷氨酰胺(polyQ)延伸赋予毒性功能增益,并导致ATXN3在神经元中的错误折叠和聚集。作为神经退行性过程的结果，SCA3患者严重残疾并过早死亡。几种筛查方法，例如，已经进行了药物全基因组和药物库筛选，集中于稳定过表达的ATXN3（polyQ）蛋白的减少和由此产生的毒性的改善。然而，毒性ATXN3的转基因过表达模型，错过了内源性ATXN3调节的潜在调节剂。在使用CRISPR/Cas9修饰的SK-N-SH野生型细胞系鉴定内源ATXN3表达的修饰剂的另一种方法中,在内源ATXN3启动子的控制下,使用GFP-T2A-荧光素酶(LUC)盒,四种他汀类药物被鉴定为潜在的表达激活剂。我们在这里提供了高通量筛选方法的概述，这些方法在不同的SCA3模型生物和细胞系中找到ATXN3（polyQ）毒性的化合物或基因组修饰剂，以改善和阻止患者的SCA3进展。此外，讨论了胆固醇在神经退行性疾病（NDDs）中的一般作用，特别是SCA3。
