Molecular Basis of Pathogenic Cascades in ALS/FTD Initiated from C9orf72 Hexanucleotide Repeat Expansion

Project Summary Nucleotide repeat elements, including microsatellites or short tandem repeats, are common in eukaryotic genomes. Expansions of short nucleotide repeats have been linked to over 50 different types of genetic disorders, primarily neurological and neuromuscular disorders. Our understanding of how these repeat elements in the human genome cause diseases is still in its infancy. A hexanucleotide repeat expansion in a noncoding region of the C9orf72 gene has been linked to the neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). ALS is characterized by loss of motor neurons, and the C9orf72 hexanucleotide repeat expansion represents the most common genetic cause of both familial and sporadic ALS. FTD is characterized by degeneration of the frontal and temporal lobes of the brain and is the second-most common type of dementia in people older than 65; the C9orf72 hexanucleotide repeat expansion is also the most common genetic cause of FTD. This repeat expansion is also found to contribute to Alzheimer’s disease and Huntington’s disease. To help relieve the public health burden associated with these diseases, it is important to understand the mechanisms underlying their pathogenesis. Multiple hypotheses exist to explain the pathogenic mechanisms underlying C9orf72-linked ALS/FTD. The goal of the proposed project is to elucidate novel mechanisms through which the C9orf72 hexanucleotide repeat expansion leads to molecular defects and neuronal toxicity, focusing on gain-of-function mechanisms. The specific aims are to identify previously unknown pathogenic cascades initiated by the C9orf72 hexanucleotide repeat expansion. These novel pathogenic cascades include, but are not limited to, RNA toxicity and non-canonical translation products resulting from the C9orf72 hexanucleotide repeat expansion. We propose a series of fundamental studies that combine biochemical, molecular, and genetic approaches to shed light on the novel pathways leading to ALS/FTD pathogenesis and to identify potential intervention strategies. Successful completion of the project is expected to provide insights into fundamental mechanisms of neurodegeneration in ALS/FTD that may ultimately lead to novel approaches for treating ALS/FTD and other relevant neurodegenerative diseases.