Department of Neurology and Stroke Medicine, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, 236-0004, Japan.
Department of Neurology, Yokohama Minami Kyosai Hospital, 1-21-1 Mutuurahigashi, Kanazawa-ku, Yokohama, 236-0037, Japan.
Mol Brain. 2021 Mar 23;14(1):59. doi: 10.1186/s13041-021-00770-1.
Intracellular aggregates are a common pathological hallmark of neurodegenerative diseases such as polyglutamine (polyQ) diseases, amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), and multiple system atrophy (MSA). Aggregates are mainly formed by aberrant disease-specific proteins and are accompanied by accumulation of other aggregate-interacting proteins. Although aggregate-interacting proteins have been considered to modulate the formation of aggregates and to be involved in molecular mechanisms of disease progression, the components of aggregate-interacting proteins remain unknown. In this study, we showed that small glutamine-rich tetratricopeptide repeat-containing protein alfa (SGTA) is an aggregate-interacting protein in neurodegenerative diseases. Immunohistochemistry showed that SGTA interacted with intracellular aggregates in Huntington disease (HD) cell models and neurons of HD model mice. We also revealed that SGTA colocalized with intracellular aggregates in postmortem brains of patients with polyQ diseases including spinocerebellar ataxia (SCA)1, SCA2, SCA3, and dentatorubral-pallidoluysian atrophy. In addition, SGTA colocalized with glial cytoplasmic inclusions in the brains of MSA patients, whereas no accumulation of SGTA was observed in neurons of PD and ALS patients. In vitro study showed that SGTA bound to polyQ aggregates through its C-terminal domain and SGTA overexpression reduced intracellular aggregates. These results suggest that SGTA may play a role in the formation of aggregates and may act as potential modifier of molecular pathological mechanisms of polyQ diseases and MSA.
细胞内聚集体是神经退行性疾病（如多聚谷氨酰胺（polyQ）疾病、肌萎缩侧索硬化症（ALS）、帕金森病（PD）和多系统萎缩（MSA））的常见病理特征。聚集体主要由异常的疾病特异性蛋白形成，并伴有其他聚集体相互作用蛋白的积累。尽管聚集体相互作用蛋白被认为可以调节聚集体的形成，并参与疾病进展的分子机制，但聚集体相互作用蛋白的成分仍不清楚。在这项研究中，我们表明，小谷氨酰胺富含四肽重复蛋白 alfa（SGTA）是神经退行性疾病中的一种聚集体相互作用蛋白。免疫组织化学显示，SGTA 与亨廷顿病（HD）细胞模型和 HD 模型小鼠神经元中的细胞内聚集体相互作用。我们还揭示了 SGTA 在包括脊髓小脑共济失调症（SCA）1、SCA2、SCA3 和齿状核红核苍白球路易体萎缩症在内的多聚 Q 疾病患者的尸检大脑中与细胞内聚集体共定位。此外，SGTA 与 MSA 患者大脑中的神经胶质细胞质包含物共定位，而在 PD 和 ALS 患者的神经元中没有观察到 SGTA 的积累。体外研究表明，SGTA 通过其 C 末端结构域与 polyQ 聚集体结合，并且 SGTA 的过表达减少了细胞内聚集体。这些结果表明，SGTA 可能在聚集体的形成中发挥作用，并可能作为多聚 Q 疾病和 MSA 的分子病理机制的潜在修饰因子。
