Sujkowski Alyson L, Ranxhi Bedri, Prifti Matthew V, Alam Nadir, Todi Sokol V, Tsou Wei-Ling
bioRxiv. 2023 Nov 11:2023.11.07.566106. doi: 10.1101/2023.11.07.566106.
Spinocerebellar ataxia type 7 (SCA7) is a progressive neurodegenerative disorder resulting from abnormal expansion of polyglutamine (polyQ) in its disease protein, ataxin-7 (ATXN7). ATXN7 is part of Spt-Ada-Gcn5 acetyltransferase (SAGA), an evolutionarily conserved transcriptional coactivation complex with critical roles in chromatin remodeling, cell signaling, neurodifferentiation, mitochondrial health and autophagy. SCA7 is dominantly inherited and characterized by genetic anticipation and high repeat-length instability. Patients with SCA7 experience progressive ataxia, atrophy, spasticity, and blindness. There is currently no cure for SCA7, and therapies are aimed at alleviating symptoms to increase quality of life. Here, we report novel lines of SCA7 with polyQ repeats in wild-type and human disease patient range. We find that ATXN7 expression has age- and polyQ repeat length-dependent reduction in survival and retinal instability, concomitant with increased ATXN7 protein aggregation. These new lines will provide important insight on disease progression that can be used in the future to identify therapeutic targets for SCA7 patients.
7型脊髓小脑共济失调（SCA7）是一种进行性神经退行性疾病，由其疾病蛋白ataxin-7（ATXN7）中的多聚谷氨酰胺（polyQ）异常扩增引起。ATXN7是Spt-Ada-Gcn5乙酰转移酶（SAGA）的一部分，SAGA是一种进化保守的转录共激活复合物，在染色质重塑、细胞信号传导、神经分化、线粒体健康和自噬中起关键作用。SCA7为常染色体显性遗传，具有遗传早现和高重复长度不稳定性的特征。SCA7患者会出现进行性共济失调、萎缩、痉挛和失明。目前SCA7尚无治愈方法，治疗旨在缓解症状以提高生活质量。在此，我们报告了野生型和人类疾病患者范围内具有polyQ重复序列的新型SCA7品系。我们发现，ATXN7表达在生存和视网膜不稳定性方面具有年龄和polyQ重复长度依赖性降低，同时伴有ATXN7蛋白聚集增加。这些新的品系将为疾病进展提供重要见解，未来可用于确定SCA7患者的治疗靶点。
