잠시만 기다려 주세요. 로딩중입니다.

C9orf72-Associated Arginine-Rich Dipeptide Repeat Proteins Reduce the Number of Golgi Outposts and Dendritic Branches in Drosophila Neurons

Molecules and Cells 2020년 43권 9호 p.821 ~ 830
박정향, Chung Chang-Geon, Seo Jin-Soo, 이병훈, 이영삼, Kweon Jung-Hyun, 이성배,
소속 상세정보
박정향 ( Park Jeong-Hyang ) - Daegu Gyeongbuk Institute of Science and Technology Department of Brain and Cognitive Sciences
 ( Chung Chang-Geon ) - Daegu Gyeongbuk Institute of Science and Technology Department of Brain and Cognitive Sciences
 ( Seo Jin-Soo ) - Daegu Gyeongbuk Institute of Science and Technology Department of Brain and Cognitive Sciences
이병훈 ( Lee Byung-Hoon ) - Daegu Gyeongbuk Institute of Science and Technology Department of Brain and Cognitive Sciences
이영삼 ( Lee Young-Sam ) - DGIST Department of New Biology
 ( Kweon Jung-Hyun ) - Daegu Gyeongbuk Institute of Science and Technology Department of Brain and Cognitive Sciences
이성배 ( Lee Sung-Bae ) - Daegu Gyeongbuk Institute of Science and Technology Department of Brain and Cognitive Sciences

Abstract


Altered dendritic morphology is frequently observed in various neurological disorders including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), but the cellular and molecular basis underlying these pathogenic dendritic abnormalities remains largely unclear. In this study, we investigated dendritic morphological defects caused by dipeptide repeat protein (DPR) toxicity associated with G4C2 expansion mutation of C9orf72 (the leading genetic cause of ALS and FTD) in Drosophila neurons and characterized the underlying pathogenic mechanisms. Among the five DPRs produced by repeat-associated non-ATG translation of G4C2 repeats, we found that arginine-rich DPRs (PR and GR) led to the most significant reduction in dendritic branches and plasma membrane (PM) supply in Class IV dendritic arborization (C4 da) neurons. Furthermore, expression of PR and GR reduced the number of Golgi outposts (GOPs) in dendrites. In Drosophila brains, expression of PR, but not GR, led to a significant reduction in the mRNA level of CrebA, a transcription factor regulating the formation of GOPs. Overexpressing CrebA in PR-expressing C4 da neurons mitigated PM supply defects and restored the number of GOPs, but the number of dendritic branches remained unchanged, suggesting that other molecules besides CrebA may be involved in dendritic branching. Taken together, our results provide valuable insight into the understanding of dendritic pathology associated with C9-ALS/FTD.

키워드

amyotrophic lateral sclerosis; C9orf72; CrebA; dendrites; Golgi outposts

원문 및 링크아웃 정보

등재저널 정보