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Epigenetic Small Molecules Rescue Nucleocytoplasmic Transport And Dna Damage Phenotypes In C9orf72 Als/Ftd, Melina Ramic, Nadja S. Andrade, Matthew J. Rybin, Rustam Esanov, Claes Wahlestedt, Michael Benatar, Zane Zeier

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Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurodegenerative disease with available treatments only marginally slowing progression or improving survival. A hexanu-cleotide repeat expansion mutation in the C9ORF72 gene is the most commonly known genetic cause of both sporadic and familial cases of ALS and frontotemporal dementia (FTD). The C9ORF72 expansion mutation produces five dipeptide repeat proteins (DPRs), and while the mechanistic determinants of DPR-mediated neurotoxicity remain incompletely understood, evidence suggests that disruption of nucleocytoplasmic transport and increased DNA damage contributes to pathology. Therefore, characterizing these disturbances and determining the relative contribution of different DPRs is needed to facilitate …