Neurological disorders are one of the leading cause of disability and death worldwide. Our goal is to obtain a better understanding of defects in neuronal DNA repair, and to exploit this knowledge to identify new vulnerabilities in neurodegeneration. The nervous system is highly susceptible to all forms of stress, including DNA damage, due to its large energy requirements, high transcriptional activity, and the long lifespan of these cells. Data suggests that mutations in DNA repair genes are associated with several neurological abnormalities and somatic tri/dinucleotide expansions, which plays a critical role in the development of neurodegenerative diseases such as Huntington’s disease (HD), or Amyotrophic lateral sclerosis (ALS). Neurons can repair and protect their genome against DNA damage under physiological conditions despite lacking DNA replication, which limits their opportunity for DNA repair. What remains in question, however, are the underlying molecular mechanisms behind these repair processes and how these non-renewable cells maintain their genomic integrity over many decades of life.