Investigating the Novel Disease Pathways Associated with C9orf72-Linked ALS/FTD

Project Summary Neurodegeneration is an increasing public health issue and remains an unsolved biomedical challenge. Genetic discoveries have provided new avenues for investigating the molecular mechanisms of several neurodegenerative diseases. A hexanucleotide repeat expansion in a noncoding region of the C9orf72 gene was linked to the neurodegenerative disease amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). ALS is characterized by loss of motor neurons, and the C9orf72 mutation 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 for people younger than 65; the C9orf72 mutation is also the most common genetic causes for FTD. The C9orf72 mutation is also found to contribute to Alzheimer’s disease and Huntington’s disease. Despite intense efforts and rapid advances, our understanding of the disease mechanisms and treatment strategies for C9orf72-linked ALS/FTD are still at the early stages. To help relieve the public health burden associated with these diseases, it is important to understand the mechanisms underlying the pathogenesis. We have recently discovered that C9orf72 is localized to specific cellular compartments, suggesting that further studies of basic C9orf72 functions as well as gained toxicity arising from the expanded repeat could shed light on the mechanism of ALS/FTD pathogenesis. The long-term goal of the proposed project is to elucidate the mechanisms through which dysregulation of C9orf72 functions and the repeat expansion leads to molecular defects and neuronal toxicity. The aims are to identify and characterize a novel function of C9orf72, to delineate the pathways C9orf72 expression is regulated, and to uncover the mechanisms of the other pathologies associated with the C9orf72 repeat. The proposed studies, which combine biochemical, molecular, and genetic approaches, are expected to provide insight into fundamental mechanisms of neurodegeneration in ALS/FTD that may ultimately leads to novel approaches for treating these devastating neurodegenerative diseases.