SRSF1-dependent nuclear export of C9ORF72 repeat transcripts: targeting toxic gain-of-functions induced by protein sequestration as a selective therapeutic strategy for neuroprotection

Microsatellite repeat expansions cause several incurable and lethal neurodegenerative disorders including , myotonic dystrophy, Huntington's disease and C9ORF72-linked amyotrophic lateral sclerosis (ALS) and dementia (FTD). Abnormal repeat transcripts generated from the expanded loci are substrates repeat-associated non-AUG (RAN) translation, an unconventional form of translation leading to the of polymeric repeat proteins with cytotoxic and aggregating properties. The mechanisms involved in pathogenesis of microsatellite repeat expansion disorders remain a hotly debated topic. They are shared toxic loss/gain of functions due to intranuclear RNA foci that sequesters RNA-binding proteins and translation of repeat proteins in the cytoplasm. We recently elucidated the molecular mechanism driving nuclear export of C9ORF72 repeat transcripts and showed for the first time that this pathway can be to confer neuroprotection. Strikingly, we discovered that intron-retaining C9ORF72 repeat hijack the physiological NXF1-dependent export pathway by selective RNA-repeat sequestration of 1. Antagonizing SRSF1 and the nuclear export of C9ORF72 repeat transcripts promoted in turn the of patient-derived motor neurons and suppressed neurodegeneration-associated motor deficits in (Hautbergue et al. Nature Communications 2017; 8:16063). In this invited Research Highlight review, aim to place this work in the context of our previous studies on the nuclear export of mRNAs, provide a of the published research and highlight the significance of these findings as a novel therapeutic for neuroprotection in C9ORF72-ALS/FTD. In addition, we emphasize that protein sequestration, often as of inducing loss-of-function mechanisms, can also trigger unwanted protein interactions and toxic -of-functions.