C9orf72-dependent lysosomal functions regulate epigenetic control of autophagy and lipid metabolism.

Cellular adaption to nutrient stress is exquisitely regulated, and its dysregulation could underlie human diseases including neurodegeneration. C9orf72 is linked to the most common forms of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) as well as rare cases of other neurological disorders. Recent studies have implicated C9orf72 functions in the autophagy-lysosome pathway, but the exact roles of C9orf72 remain unclear. We found that C9orf72 is required for the lysosomal targeting and degradation of CARM1, which is an important epigenetic regulator of macroautophagy/autophagy and lipid metabolism. In cells with C9orf72 deficiency including those derived from ALS-FTD patients, CARM1 is abnormally accumulated especially under glucose starvation stress, leading to dysregulated autophagy and lipid metabolism. These findings suggest that C9orf72 is a key regulator in the negative feedback control of the autophagy-lysosome pathway during nutrient stress responses.