The spinocerebellar ataxia type 2 (SCA2) gene ATXN2 has a prominent role in the pathogenesis and treatment of amyotrophic lateral sclerosis (ALS). In addition to cerebellar ataxia, motor neuron disease is often seen in SCA2, and ATXN2 CAG repeat expansions in the long normal range increase ALS risk. Also, lowering ATXN2 expression in TDP-43 ALS mice prolongs their survival. Here we investigated the ATXN2 relationship with motor neuron dysfunction in vivo by comparing spinal cord (SC) transcriptomes reported from TDP-43 and SOD1 ALS mice and ALS patients with those from SCA2 mice. SC transcriptomes were determined using an SCA2 bacterial artificial chromosome mouse model expressing polyglutamine expanded ATXN2. SCA2 cerebellar transcriptomes were also determined, and we also investigated the modification of gene expression following treatment of SCA2 mice with an antisense oligonucleotide (ASO) lowering ATXN2 expression. Differentially expressed genes (DEGs) defined three interconnected pathways (innate immunity, fatty acid biosynthesis and cholesterol biosynthesis) in separate modules identified by weighted gene co-expression network analysis. Other key pathways included the complement system and lysosome/phagosome pathways. Of all DEGs in SC, 12.6% were also dysregulated in the cerebellum. Treatment of mice with an ATXN2 ASO also modified innate immunity, the complement system and lysosome/phagosome pathways. This study provides new insights into the underlying molecular basis of SCA2 SC phenotypes and demonstrates annotated pathways shared with TDP-43 and SOD1 ALS mice and ALS patients. It also emphasizes the importance of ATXN2 in motor neuron degeneration and confirms ATXN2 as a therapeutic target.

中文翻译：

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SCA2 小鼠脊髓转录组中的 ALS 相关基因。

脊髓小脑性共济失调 2 型 (SCA2) 基因ATXN2在肌萎缩侧索硬化 (ALS) 的发病机制和治疗中具有重要作用。除了小脑性共济失调，运动神经元疾病也常出现在 SCA2 中，而ATXN2 CAG 在长正常范围内的重复扩增会增加 ALS 风险。此外，降低TDP-43 ALS 小鼠的ATXN2表达可延长其存活时间。在这里，我们通过比较 TDP-43 和 SOD1 ALS 小鼠和 ALS 患者与 SCA2 小鼠报告的脊髓 (SC) 转录组，研究了 ATXN2 与体内运动神经元功能障碍的关系。SC 转录组是使用 SCA2 细菌人工染色体小鼠模型确定的，该模型表达了多聚谷氨酰胺扩增的ATXN2. 还确定了 SCA2 小脑转录组，我们还研究了用降低ATXN2表达的反义寡核苷酸 (ASO) 治疗 SCA2 小鼠后基因表达的修饰。差异表达基因 (DEG) 在通过加权基因共表达网络分析确定的单独模块中定义了三个相互关联的途径（先天免疫、脂肪酸生物合成和胆固醇生物合成）。其他关键途径包括补体系统和溶酶体/吞噬体途径。在 SC 的所有 DEG 中，12.6% 在小脑中也失调。用ATXN2治疗小鼠ASO 还修改了先天免疫、补体系统和溶酶体/吞噬体途径。这项研究为 SCA2 SC 表型的潜在分子基础提供了新的见解，并展示了与 TDP-43 和 SOD1 ALS 小鼠和 ALS 患者共享的注释通路。它还强调了 ATXN2 在运动神经元变性中的重要性，并确认了 ATXN2 作为治疗靶点。