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

The ALS-FTD-linked gene product, C9orf72, regulates neuronal morphogenesis via autophagy. Autophagy. 2019 Jan 23;: Authors: Ho WY, Tai YK, Chang JC, Liang J, Tyan SH, Chen S, Guan JL, Zhou H, Shen HM, Koo E, Ling SC Abstract 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 o...
Source: Autophagy - Category: Cytology Authors: Tags: Autophagy Source Type: research