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.
See also: C Sellier et al
When GGGGCC (G4C2) repeat expansions in the first intron of C9ORF72 were identified as the most common genetic cause of ALS and FTD (DeJesus‐Hernandez et al, 2011; Renton et al, 2011), nothing was known about the molecular functions of C9ORF72. Since then, breathtaking progress has been made in understanding the effects of this mutation, largely focusing on the toxic products derived from expanded G4C2 repeats (Gitler & Tsuiji, 2016). For instance, the expanded repeats in nuclear RNA foci might misregulate RNA processing by sequestering some RNA‐binding proteins. Moreover, abnormal translation of the sense and antisense repeat RNAs through a repeat‐associated non‐AUG (RAN) translation mechanism gives rise to toxic dipeptide repeat (DPR) proteins. However, expression of C9ORF72 mRNA is also reduced in ALS/FTD patients with C9ORF72 repeat expansions—raising the possibility that compromised C9ORF72 …
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