Abstract

Accelerated aging disorders represent a phenotypically diverse group of diseases all with defects in DNA maintenance. In a subset of these disorders, neurodegeneration is prominent. Notably, the neurological phenotype is strikingly similar to what is seen in primary mitochondrial disorders, an observation that we have investigated and corroborated using in silico, in vitro and in vivo methods. The mitochondrial dysfunction in these neurodegenerative diseases may be caused by hyperactivation of a nuclear DNA damage response involving the enzyme poly-ADP-ribose-polymerase 1 (PARP1) leading to loss of NAD and alterations in cellular and organismal metabolism. Interventions at steps in this pathway lead to normalization of the mitochondrial phenotypes suggesting that new treatments may be possible for these, previously, untreatable disorders.