Transcriptional changes in mouse models in SCA3

The study examined early transcriptional changes in the brain of different mouse models of spinocerebellar ataxia type 3, a dominantly-inherited neurodegenerative disease caused by a CAG repeat expansion in the ATXN3 gene. The goal was to identify early transcriptional signatures that are strongly associated with the accumulation and aggregation of the disease protein, ataxin-3, in the brain. The study also investigated the extent to which the observed transcriptional changes might be contributors to disease pathogenesis. The overall study includes multiple different RNA-seq runs utilizing wild-type, two different knock-in mouse models of SCA3 (a traditional and variant), two different transgenic models of SCA3 (Q84 and Q15), and an ataxin-3 knock-out mouse. In total, 19 wild-type mice, 13 homozygous variant knock-in mice, 6 heterozygous variant knock-in mice, 4 traditional homozygous knock-in mice, 4 traditional heterozygous knock-in mice, 4 Q84 transgenic mice, 4 Q15 transgenic mice, and 3 ataxin-3 knock-out mice. The majority of the study examined the pons of the mice, and with one smaller run examining the deep cerebellar nuclei of wild-type and variant homozygous knock-in mice (n=3 each).本研究针对脊髓小脑共济失调3型（spinocerebellar ataxia type 3, SCA3）展开相关实验，该疾病是由ATXN3基因（ATXN3 gene）内CAG重复扩增（CAG repeat expansion）所导致的显性遗传性神经退行性疾病。本研究旨在鉴定与脑内疾病蛋白共济失调蛋白3（ataxin-3）的积累与聚集紧密相关的早期转录特征，同时探究观测到的转录变化在疾病发病机制中的潜在贡献程度。本研究共开展多组RNA测序（RNA-seq）实验，所用小鼠模型涵盖野生型（wild-type）、2种SCA3基因敲入（knock-in）小鼠模型（传统型与变异型）、2种SCA3转基因（transgenic）小鼠模型（Q84与Q15），以及1株共济失调蛋白3基因敲除（ataxin-3 knock-out）小鼠。实验总样本量如下：野生型小鼠19只、纯合变异型基因敲入小鼠13只、杂合变异型基因敲入小鼠6只、传统型纯合基因敲入小鼠4只、传统型杂合基因敲入小鼠4只、Q84转基因小鼠4只、Q15转基因小鼠4只，以及共济失调蛋白3基因敲除小鼠3只。本研究的主体实验以小鼠脑桥（pons）为检测靶区，另有一项小型实验针对野生型与变异型纯合基因敲入小鼠的小脑深部核团（deep cerebellar nuclei）开展检测，每组各3只小鼠。