Abstract
A hexanucleotide repeat expansion in the C9ORF72 gene is the most common genetic alteration associated with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). These neurodegenerative diseases share genetic, clinical and pathological features. The mutation in C9ORF72 appears to drive pathogenesis through a combination of loss of C9ORF72 normal function and gain of toxic effects due to the repeat expansion, which result in aggregation prone expanded RNAs and dipeptide repeat (DPR) proteins. Studies in cellular and animal models indicate that the DPR proteins are the more toxic species. Thus, a large body of research has focused on identifying the cellular pathways most directly impacted by these toxic proteins, with the goal of characterizing disease pathogenesis and nominating potential targets for therapeutic development. The preventative block of the production of the toxic proteins before they can cause harm is a second strategy of intense focus. Despite the considerable amount of effort dedicated to this prophylactic approach, it is still unclear how the DPR proteins are synthesized from RNAs harboring repeat expansions. In this review, we summarize our current knowledge of the specific protein translation mechanisms shown to account for the synthesis of DPR proteins. We will then discuss how enhanced understanding of the composition of these toxic effectors could help in refining disease mechanisms, and paving the way to identify and design effective prophylactic therapies for C9ORF72 ALS-FTD.