Nanoscopic investigation of C9orf72 poly-GA oligomers on nuclear membrane disruption by a photoinducible platform

Hung Ming Chien, Ruei Yu He, Chi Chang Lee, Yung An Huang, I. Ju Hung, Kai Ting Hou, Jye Chian Hsiao, Po Chao Lu, Diksha Agnihotri, Eric Hwang, Joseph Jen Tse Huang*

*此作品的通信作者

研究成果: Article同行評審

1 引文 斯高帕斯(Scopus)

摘要

Glycine-alanine dipeptide repeats (GA DPRs) translated from the mutated C9orf72 gene have recently been correlated with amyotrophic lateral sclerosis (ALS). While GA DPRs aggregates have been suggested as amyloid, the biophysical features and cytotoxicity of GA DPRs oligomers has not been explored due to its unstable nature. In this study, we develop a photoinducible platform based on methoxynitrobenzene chemistry to enrich GA DPRs that allows monitoring the oligomerization process of GA DPRs in cells. By applying advanced microscopies, we examined the GA DPRs oligomerization process nanoscopically in a time-dependent manner. We provided direct evidences to demonstrate GA DPRs oligomers rather than nanofibrils disrupt nuclear membrane. Moreover, we found GA DPRs hamper nucleocytoplasmic transport in cells and cause cytosolic retention of TAR DNA-binding protein 43 in cortical neurons. Our results highlight the toxicity of GA DPRs oligomers, which is a key step toward elucidating the pathological roles of C9orf72 DPRs.

原文English
文章編號111
期刊Communications Chemistry
4
發行號1
DOIs
出版狀態Published - 12月 2021

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