Hexanucleotide expansions in the C9orf72 gene cause ~50% of all familial ALS cases. The mechanism(s) by which this expansion causes disease are not known. Current hypotheses to explain the disease mechanism include haploinsufficiency and gain-of-function RNA and/or protein toxicity. Despite its presence in an intron, the disease causing expansion is translated into protein in multiple reading frames from both the sense and anti-sense strands to produce five distinct dipeptide proteins. Expression of each of these dipeptides has been specifically detected in ALS patient samples. Several recent studies, as well as our own data, show that the arginine dipeptides exhibit substantial neurotoxicity through unknown mechanisms. Here, we will use genetic screening in C. elegans, followed by validation in Drosophila and mammalian cells, to identify these mechanisms. Our studies will provide significant new insights into the pathways by which dipeptides engages and kill motor neurons and may identify novel risk factors and new therapeutic targets for treating this currently incurable disease
Hexanucleotide expansions in the C9orf72 represent the single largest known neurodegenerative disease-causing mutation, which is most commonly associated with ALS and frontotemporal dementia. Nothing is known about the pathways that connect this mutation to neurodegenerative disease. Our studies will define clinically relevant mechanisms that allow C9orf72 mutations to cause neurodegeneration, some of which might be leveraged to treat or better diagnose these currently incurable diseases.
