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Cited 3 time in webofscience Cited 4 time in scopus
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C9orf72-associated arginine-rich dipeptide repeats induce RNA-dependent nuclear accumulation of Staufen in neurons

Authors
Kim, Eun SeonChung, Chang GeonPark, Jeong HyangKo, Byung SuPark, Sung SoonKim, Yoon HaCha, In JunKim, JaekwangHa, Chang ManKim, Hyung-JunLee, Sung Bae
Issue Date
Jun-2021
Publisher
OXFORD UNIV PRESS
Citation
HUMAN MOLECULAR GENETICS, v.30, no.12, pp 1084 - 1100
Pages
17
Journal Title
HUMAN MOLECULAR GENETICS
Volume
30
Number
12
Start Page
1084
End Page
1100
URI
http://scholarworks.bwise.kr/kbri/handle/2023.sw.kbri/322
DOI
10.1093/hmg/ddab089
ISSN
0964-6906
1460-2083
Abstract
RNA-binding proteins (RBPs) play essential roles in diverse cellular processes through post-transcriptional regulation of RNAs. The subcellular localization of RBPs is thus under tight control, the breakdown of which is associated with aberrant cytoplasmic accumulation of nuclear RBPs such as TDP-43 and FUS, well-known pathological markers for amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD). Here, we report in Drosophila model for ALS/FTD that nuclear accumulation of a cytoplasmic RBP Staufen may be a new pathological feature. We found that in Drosophila C4da neurons expressing PR36, one of the arginine-rich dipeptide repeat proteins (DPRs), Staufen accumulated in the nucleus in Importin-and RNA-dependent manner. Notably, expressing Staufen with exogenous NLS-but not with mutated endogenous NLS-potentiated PR-induced dendritic defect, suggesting that nuclear-accumulated Staufen can enhance PR toxicity. PR36 expression increased Fibrillarin staining in the nucleolus, which was enhanced by heterozygous mutation of stau (stau(+/-)), a gene that codes Staufen. Furthermore, knockdown of fib, which codes Fibrillarin, exacerbated retinal degeneration mediated by PR toxicity, suggesting that increased amount of Fibrillarin by stau(+/-) is protective. stau(+/-) also reduced the amount of PR-induced nuclear-accumulated Staufen and mitigated retinal degeneration and rescued viability of flies expressing PR36. Taken together, our data show that nuclear accumulation of Staufen in neurons may be an important pathological feature contributing to the pathogenesis of ALS/FTD.
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Kim, Jae kwang
연구본부 (치매 연구그룹)
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