Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are neurodegenerative diseases with clinical, pathological and genetic overlap. The expansion of a hexanucleotide repeat in a non-coding region of C9ORF72 is the major genetic cause of FTD and ALS. Elucidating how these expanded repeats cause """"""""c9FTD/ALS"""""""" has since become an important goal of the field. Our recent study identifying a new pathological hallmark of c9FTD/ALS - the accumulation of neuronal inclusions composed of peptides produced by repeat associated non-ATG (RAN) translation of sense and antisense transcripts of the expanded repeat - implicates RAN translation as a mechanism of disease. This unconventional mode of translation was first described for expanded CAG?CTG repeats and accounts for the accumulation of polyA or polyQ proteins in spinocerebellar ataxia type 8 and myotonic dystrophy type 1, respectively. Based on our findings that RAN translation of expanded repeats similarly occurs in c9FTD/ALS, we believe that peptides thusly produced play a role in disease pathogenesis. This project aims to investigate this pressing question, as well as several others. Specifically, we will evaluate whether: 1) the various peptides produced via RAN translation show a differential pattern of expression in c9FTD/ALS;2) there is differential toxicity among RAN translated peptides or among soluble and insoluble species;3) toxicity is enhanced by loss of C9ORF72 function;and 4) expression of RAN translated peptides influences disease phenotype or depend upon repeat length. To investigate these questions we will utilize novel antibodies, develop new cell culture and animal models, and examine fibroblasts and tissues from c9FTD/ALS patients. In addition to being subject to RAN translation, accumulating sense (GGGGCC)exp and antisense (CCCCGG)exp RNA transcripts may result in the sequestration of RNA-binding proteins in c9FTD/ALS. Nuclear RNA foci of expanded RNA transcripts accumulate in frontal cortex, spinal cord and cerebellum of C9ORF72 repeat expansion carriers. The sequestration and inactivation of RNA- binding proteins by RNA foci is observed in several repeat expansion diseases and is thought to account for some features of disease. The identification of RNA-binding proteins sequestered by transcripts of expanded repeats in C9ORF72, and determining whether the function of these proteins are altered in c9FTD/ALS, will increase our understanding of this potential mechanism of disease. Overall, the goals of Project 2 are to test the hypothesis that transcripts of expanded repeats contribute to c9FTD/ALS pathogenesis via two mechanisms: by RAN translation and by the mis-regulation of RNA-binding proteins.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
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National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
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Mayo Clinic Jacksonville
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Nicolas, Aude (see original citation for additional authors) (2018) Genome-wide Analyses Identify KIF5A as a Novel ALS Gene. Neuron 97:1268-1283.e6
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