Lost & found: C9 ORF 72 and the autophagy pathway in ALS / FTD

C9 ORF 72 expression is reduced in a substantial number of patients with amyotrophic lateral sclerosis ( ALS ) and frontotemporal dementia ( FTD ), which may contribute to disease pathogenesis. However, its normal molecular function remains unknown. In this issue of The EMBO Journal , Sellier et al ([Sellier C, 2016]) identified a novel protein complex consisting of C9 ORF 72, WDR 41, and SMCR 8 that acts as a GDP ‐ GTP exchange factor ( GEF ) for RAB 8a and RAB 39b and is regulated by TBK 1, whose partial loss of function also causes ALS and FTD . They further reveal a potential modulatory role for this novel complex in macroautophagy (autophagy), especially in the context of ataxin‐2 toxicity.