The ALS-FTD-linked gene product, C9orf72, regulates neuronal morphogenesis via autophagy

• DOI: 10.1080/15548627.2019.1569441
• Publication Date: 2019-01-24T07:28:07Z
• Authors: Wan Yun Ho; Yee Kit Tai; Jer-Cherng Chang; Jason Liang; Sheue-Houy Tyan; Song Chen; Jun-Lin Guan; Huilin Zhou; Han-Ming Shen; Edward Koo; Shuo-Chien Ling
• Keywords: C9ORF72; Knockout mouse; Autophagy-related protein 13

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 FTD is seen transgenic mice overexpressing expansions, but absent C9orf72-deficient mice. Thus, exact function of neurons how loss may contribute neuronal dysfunction remains be clearly defined. Here, we showed that primary hippocampal cultured from c9orf72 knockout have reduced dendritic arborization spine density. Quantitative proteomic analysis identified as a component macroautophagy/autophagy initiation complex composed ULK1-RB1CC1-ATG13-ATG101. The association was mediated through direct interaction with ATG13 via isoform-specific carboxyl-terminal DENN dDENN domain C9orf72. Furthermore, LC3-II puncta accompanied by ULK1 levels, suggesting impairs basal autophagy. Conversely, wild-type treated kinase inhibitor dose-dependent reduction expression long isoform human interacts complex, not short isoform, rescues autophagy phenotypes neurons. Taken together, our data suggests has cell-autonomous role morphogenesis promotion ULK1-mediated