Verde Enza Maria, Secco Valentina, Ghezzi Andrea, Mandrioli Jessica, Carra Serena
Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, 41125 Modena, Italy.
Cells. 2025 May 8;14(10):680. doi: 10.3390/cells14100680.
Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD) are two neurodegenerative disorders that share common genes and pathomechanisms and are referred to as the ALS-FTD spectrum. A hallmark of ALS-FTD pathology is the abnormal aggregation of proteins, including Cu/Zn superoxide dismutase (SOD1), transactive response DNA-binding protein 43 (TDP-43), fused in sarcoma/translocated in liposarcoma (FUS/TLS), and dipeptide repeat proteins resulting from C9orf72 hexanucleotide expansions. Genetic mutations linked to ALS-FTD disrupt protein stability, phase separation, and interaction networks, promoting misfolding and insolubility. This review explores the molecular mechanisms underlying protein aggregation in ALS-FTD, with a particular focus on TDP-43, as it represents the main aggregated species inside pathological inclusions and can also aggregate in its wild-type form. Moreover, this review describes the protective mechanisms activated by the cells to prevent protein aggregation, including molecular chaperones and post-translational modifications (PTMs). Understanding these regulatory pathways could offer new insights into targeted interventions aimed at mitigating cell toxicity and restoring cellular function.
肌萎缩侧索硬化症（ALS）和额颞叶痴呆（FTD）是两种具有共同基因和病理机制的神经退行性疾病，被称为ALS-FTD谱系。ALS-FTD病理学的一个标志是蛋白质的异常聚集，包括铜/锌超氧化物歧化酶（SOD1）、反式激活反应DNA结合蛋白43（TDP-43）、肉瘤融合/脂肪肉瘤易位蛋白（FUS/TLS），以及由C9orf72六核苷酸扩增产生的二肽重复蛋白。与ALS-FTD相关的基因突变会破坏蛋白质的稳定性、相分离和相互作用网络，促进错误折叠和不溶性。本综述探讨了ALS-FTD中蛋白质聚集的分子机制，特别关注TDP-43，因为它是病理包涵体内主要的聚集物，并且也可以以野生型形式聚集。此外，本综述描述了细胞激活的防止蛋白质聚集的保护机制，包括分子伴侣和翻译后修饰（PTM）。了解这些调节途径可为旨在减轻细胞毒性和恢复细胞功能的靶向干预提供新的见解。
