C9orf72
氨基酸
神经退行性变
失智症
翻译(生物学)
二肽
三核苷酸重复扩增
化学
生物化学
生物
生物物理学
细胞生物学
遗传学
痴呆
医学
基因
等位基因
疾病
内科学
信使核糖核酸
作者
Kohsuke Kanekura,Yuhei Hayamizu,Masahiko Kuroda
出处
期刊:American Journal of Physiology-cell Physiology
[American Physiological Society]
日期:2021-12-15
卷期号:322 (2): C197-C204
被引量:1
标识
DOI:10.1152/ajpcell.00372.2021
摘要
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) have been thought as two distinct neurodegenerative diseases. However, recent genetic screening and careful investigations found the genetic and pathological overlap among these disorders. Hexanucleotide expansions in intron 1 of C9ORF72 are a leading cause of familial ALS and familial FTD. These expansions facilitate the repeat-associated non-ATG-initiated translation (RAN translation), producing five dipeptide repeat proteins (DRPs), including Arg-rich poly(PR: Pro-Arg) and poly(GR: Gly-Arg) peptides. Arg is a positively charged, highly polar amino acid that facilitates interactions with anionic molecules such as nucleic acids and acidic amino acids via electrostatic forces and aromatic amino acids via cation-π interaction, suggesting that Arg-rich DRPs underlie the pathophysiology of ALS via Arg-mediated molecular interactions. Arg-rich DRPs have also been reported to induce neurodegeneration in cellular and animal models via multiple mechanisms; however, it remains unclear why the Arg-rich DRPs exhibit such diverse toxic properties, because not all Arg-rich peptides are toxic. In this mini-review, we discuss the current understanding of the pathophysiology of Arg-rich C9ORF72 DRPs and introduce recent findings on the role of Arg distribution as a determinant of the toxicity and its contribution to the pathogenesis of ALS.
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