Please use this identifier to cite or link to this item: https://scholarbank.nus.edu.sg/handle/10635/155081
Title: The ALS-FTD-linked gene product, C9orf72, regulates neuronal morphogenesis via autophagy
Authors: HO, WAN YUN 
TAI, YEE KIT 
CHANG, JER-CHERNG 
LIANG, JASON
TYAN, SHEUE-HOUY 
CHEN, SONG
GUAN, JUN-LIN
ZHOU, HUILIN
SHEN, HAN-MING 
KOO, EDWARD 
LING, SHUO-CHIEN 
Keywords: Science & Technology
Life Sciences & Biomedicine
Cell Biology
Amyotrophic lateral sclerosis (ALS)
autophagy
C9orf72
dendritic arborization
frontotemporal dementia (FTD)
ULK1
AMYOTROPHIC-LATERAL-SCLEROSIS
REPEAT EXPANSION
ULK1 COMPLEX
PATHOGENIC MECHANISMS
HEXANUCLEOTIDE REPEAT
MUTATIONS
NEURODEGENERATION
DENN
RNA
RAB
Issue Date: 4-May-2019
Publisher: TAYLOR & FRANCIS INC
Citation: HO, WAN YUN, TAI, YEE KIT, CHANG, JER-CHERNG, LIANG, JASON, TYAN, SHEUE-HOUY, CHEN, SONG, GUAN, JUN-LIN, ZHOU, HUILIN, SHEN, HAN-MING, KOO, EDWARD, LING, SHUO-CHIEN (2019-05-04). The ALS-FTD-linked gene product, C9orf72, regulates neuronal morphogenesis via autophagy. AUTOPHAGY 15 (5) : 827-842. ScholarBank@NUS Repository.
Abstract: © 2019, © 2019 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. Mutations in C9orf72 leading to hexanucleotide expansions are the most common genetic causes for amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). A phenotype resembling ALS and FTD is seen in transgenic mice overexpressing the hexanucleotide expansions, but is absent in C9orf72-deficient mice. Thus, the exact function of C9orf72 in neurons and how loss of C9orf72 may contribute to neuronal dysfunction remains to be clearly defined. Here, we showed that primary hippocampal neurons cultured from c9orf72 knockout mice have reduced dendritic arborization and spine density. Quantitative proteomic analysis identified C9orf72 as a component of the macroautophagy/autophagy initiation complex composed of ULK1-RB1CC1-ATG13-ATG101. The association was mediated through the direct interaction with ATG13 via the isoform-specific carboxyl-terminal DENN and dDENN domain of C9orf72. Furthermore, c9orf72 knockout neurons showed reduced LC3-II puncta accompanied by reduced ULK1 levels, suggesting that loss of C9orf72 impairs basal autophagy. Conversely, wild-type neurons treated with a ULK1 kinase inhibitor showed a dose-dependent reduction of dendritic arborization and spine density. Furthermore, expression of the long isoform of human C9orf72 that interacts with the ULK1 complex, but not the short isoform, rescues autophagy and the dendritic arborization phenotypes of c9orf72 knockout neurons. Taken together, our data suggests that C9orf72 has a cell-autonomous role in neuronal and dendritic morphogenesis through promotion of ULK1-mediated autophagy.
Source Title: AUTOPHAGY
URI: https://scholarbank.nus.edu.sg/handle/10635/155081
ISSN: 15548627
15548635
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