Many neurodegenerative diseases are linked to known, often highly or completely penetrant genetic abnormalities. The cellular pathology that follows from these genetic abnormalities to cause disease is often poorly understood, which has hindered the development of effective therapeutic interventions. Repeat sequence expansions in somatic cells of the central nervous system are linked to several dozen distinct neuropsychiatric disorders, including Huntington’s disease (HD), ataxia’s, ALS, and frontotemporal dementia (FTD). Currently there are no treatments that can alter the course of these severe and often fatal diseases. The genes associated with these disorders vary, however, shared sequence features suggest a potentially common mechanism may underlie the disease pathology of many. Using genome editing technologies, we modify nucleotide sequences implicated in these diseases and use genomic, transcriptomic and proteomic assays to gain insight into the molecular changes that underlie neurodegeneration.