Integrative Molecular and Biomedical Science Program, and.
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
J Clin Invest. 2022 May 2;132(9). doi: 10.1172/JCI156616.
Many neurodegenerative disorders are caused by abnormal accumulation of misfolded proteins. In spinocerebellar ataxia type 1 (SCA1), accumulation of polyglutamine-expanded (polyQ-expanded) ataxin-1 (ATXN1) causes neuronal toxicity. Lowering total ATXN1, especially the polyQ-expanded form, alleviates disease phenotypes in mice, but the molecular mechanism by which the mutant ATXN1 is specifically modulated is not understood. Here, we identified 22 mutant ATXN1 regulators by performing a cross-species screen of 7787 and 2144 genes in human cells and Drosophila eyes, respectively. Among them, transglutaminase 5 (TG5) preferentially regulated mutant ATXN1 over the WT protein. TG enzymes catalyzed cross-linking of ATXN1 in a polyQ-length-dependent manner, thereby preferentially modulating mutant ATXN1 stability and oligomerization. Perturbing Tg in Drosophila SCA1 models modulated mutant ATXN1 toxicity. Moreover, TG5 was enriched in the nuclei of SCA1-affected neurons and colocalized with nuclear ATXN1 inclusions in brain tissue from patients with SCA1. Our work provides a molecular insight into SCA1 pathogenesis and an opportunity for allele-specific targeting for neurodegenerative disorders.
许多神经退行性疾病是由错误折叠蛋白的异常积累引起的。在脊髓小脑共济失调 1 型（SCA1）中，聚谷氨酰胺扩展（polyQ 扩展）ataxin-1（ATXN1）的积累导致神经元毒性。降低总 ATXN1，特别是 polyQ 扩展形式，可减轻小鼠的疾病表型，但突变 ATXN1 被特异性调节的分子机制尚不清楚。在这里，我们通过在人类细胞和果蝇眼中分别进行 7787 和 2144 个基因的种间筛选，鉴定了 22 个突变 ATXN1 调节剂。其中，转谷氨酰胺酶 5（TG5）优先调节突变 ATXN1 而不是 WT 蛋白。TG 酶以 polyQ 长度依赖性方式催化 ATXN1 的交联，从而优先调节突变 ATXN1 的稳定性和寡聚化。在果蝇 SCA1 模型中扰乱 Tg 可调节突变 ATXN1 的毒性。此外，TG5 在受 SCA1 影响的神经元的核中富集，并与 SCA1 患者脑组织中的核 ATXN1 包涵体共定位。我们的工作为 SCA1 发病机制提供了分子见解，并为神经退行性疾病的等位基因特异性靶向提供了机会。
