Lost & found: C9ORF72 and the autophagy pathway in ALS/FTD

Abstract

C9ORF72 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 (2016) identified a novel protein complex consisting of C9ORF72, WDR41, and SMCR8 that acts as a GDP‐GTP exchange factor (GEF) for RAB8a and RAB39b and is regulated by TBK1, 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.

Figure 1. Schematic overview of ALS/FTD disease proteins known to play a role in the autophagy and endosomal–lysosomal pathways

Sellier et al (2016) identified a novel complex consisting of C9ORF72, WDR41, and SMCR8 that serves as a GEF for RAB39b. This complex may play a modulatory role in the initiation of autophagy in certain cell types, but detailed molecular mechanisms remain unclear. Key functions of many other ALS/FTD disease proteins (in red) in some steps of the autophagy and endosomal–lysosomal pathways are also highlighted. MVB, multivesicular body.