PROJECT 1 A hexanucleotide (G4C2) repeat expansion in the C9orf72 gene is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), collectively referred to as c9ALS/FTD. Mounting evidence indicates repeat-containing transcripts cause c9ALS/FTD through gain-of-function mechanisms by producing toxic RNA foci and dipeptide repeat (DPR) proteins. Our central hypothesis in this proposal is that each of these pathologies (RNA foci, DPR proteins) elicits both common and cell-specific molecular cascades. To address this question, we will perform bulk and single-nucleus RNAseq (sn-RNAseq) using our novel c9ALS/FTD mouse model and patient tissues to uncover the whole and single-cell landscape of transcriptional changes that occur during c9ALS pathogenesis. Our single-nucleus approach will also allow us to test how an individual neuron with RNA foci and/or DPR protein pathology is different than even a neighboring neuron without apparent pathology. Moreover, we will treat our c9ALS/FTD mouse model with antisense oligonucleotides (ASO) targeting repeat-containing transcripts, which has been shown to reduce RNA foci burden, DPR protein pathology and other anomalies in various c9ALS models. Treatment will be initiated at early and late stages of disease to determine the optimal timing of ASO treatment for mitigating neuropathology, behavioral deficits, and the single-cell landscape of transcriptional changes. Our studies will identify and validate high value therapeutic targets to treat c9ALS/FTD.
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