Role of the C9ORF72 Gene in the Pathogenesis of Amyotrophic Lateral Sclerosis and Frontotemporal Dementia

AbstractSince the discovery of theC9ORF72 gene in 2011, great advances have been achieved in its genetics and in identifying its role in disease models and pathological mechanisms; it is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). ALS patients withC9ORF72 expansion show heterogeneous symptoms. Those who areC9ORF72 expansion carriers have shorter survival after disease onset than non-C9ORF72 expansion patients. Pathological and clinical features ofC9ORF72 patients have been well mimickedvia several models, including induced pluripotent stem cell-derived neurons and transgenic mice that were embedded with bacterial artificial chromosome construct and that overexpressing dipeptide repeat proteins. The mechanisms implicated inC9ORF72 pathology include DNA damage, changes of RNA metabolism, alteration of phase separation, and impairment of nucleocytoplasmic transport, which may underlieC9ORF72 expansion-related ALS/FTD and provide insight into non-C9ORF72 expansion-related ALS, FTD, and other neurodegenerative diseases.
Source: Neuroscience Bulletin - Category: Neuroscience Source Type: research