Ribosome-associated pathological TDP-43 alters the expression of multiple mRNAs in the monkey brain
Year: 2024
Type: article
Abstract: Cytoplasmic accumulation of TDP-43 is a pathological hallmark of amyotrophic lateral sclerosis (ALS) and other neurodegenerative diseases. While current studies have primarily focused on gene regulation mediated by full-length nuclear TDP-43, the potential effects of cytoplasmic TDP-43 fragments remain less explored. Our previous findings demonstrated that primate-specific cleavage of TDP-43 contributes to its cytoplasmic localization, prompting further investigation into its pathological effects. In the cynomolgus monkey brain, we observed that mutant or truncated TDP-43 was transported onto the ribosome organelle. Ribosome-associated transcriptomic analysis revealed dysregulation of apoptosis- and lysosome-related genes, indicating that cytoplasmic TDP-43 induces neurotoxicity by binding to ribosomes and disrupting mRNA expression. These findings provide mechanistic insights into the gain-of-function effects of pathological TDP-43.
Source: 动物学研究
Authors: Deng Fu-Yu, 粤港澳中枢神经再生研究院, 中枢神经再生教育部重点实验室, 广东省非人灵长类动物模型研究重点实验室, 广东 广州 510632, 中国, Zhu Gao-Lu, Ou Kai-Li, Zhu Long-Hong, Jia Qing-Qing, Wang Xiang, Guo Ming-Wei, Li Bang, Li Shi-Hua, Li Xiao-Jiang, Yin Peng, 深圳市药品检验研究院, 深圳市医疗器械检测中心, 体外诊断试剂检测部, 广东 深圳 518057, 中国
Institutions: Jinan University, Shenzhen Institute for Drug Control
Language: English
Subfield: Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: diamond
OpenAlex ID: W4404945541