C9orf72 intermediate repeats are associated with corticobasal degeneration, increased C9orf72 expression and disruption of autophagy

AbstractMicrosatellite repeat expansion disease loci can exhibit pleiotropic clinical and biological effects depending on repeat length. Large expansions inC9orf72 (100s –1000s of units) are the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal degeneration (FTD). However, whether intermediate expansions also contribute to neurodegenerative disease is not well understood. Several studies have identified intermediate repeats in Par kinson’s disease patients, but the association was not found in autopsy-confirmed cases. We hypothesized that intermediateC9orf72 repeats are a genetic risk factor for corticobasal degeneration (CBD), a neurodegenerative disease that can be clinically similar to Parkinson ’s but has distinct tau protein pathology. Indeed, intermediateC9orf72 repeats were significantly enriched in autopsy-proven CBD (n = 354 cases, odds ratio = 3.59,p = 0.00024). While largeC9orf72 repeat expansions are known to decreaseC9orf72 expression, intermediateC9orf72 repeats result in increasedC9orf72 expression in human brain tissue and CRISPR/cas9 knockin iPSC-derived neural progenitor cells. In contrast to cases of FTD/ALS with largeC9orf72 expansions, CBD with intermediateC9orf72 repeats was not associated with pathologic RNA foci or dipeptide repeat protein aggregates. Knock-in cells with intermediate repeats exhibit numerous changes in gene expression pathways relating to vesicle trafficking and autophagy. Additionall...

Source: Acta Neuropathologica - July 19, 2019 Category: Neurology Source Type: research