DNA repair: A unifying mechanism in neurodegeneration.

Abstract

Identification of a previously uncharacterized genetic disease highlights DNA repair as a shared mechanism in neurodegenerative disorders, and suggests potential therapeutic approaches to tackling them. See Letter p.87 This paper shows that mutated forms of human XRCC1, a scaffold protein involved in DNA single-strand break repair, are associated with ocular motor apraxia, axonal neuropathy, and progressive cerebellar ataxia. In cells from a patient with an XRCC1−/− mutation, rates of break repair are reduced and the single-strand break sensor protein PARP1 is hyperactivated, resulting in abnormally high levels of cellular ADP-ribose. Genetic deletion of Parp1 in Xrcc1-defective mice prevents the accumulation of excessive ADP-ribose and rescues the loss of cerebellar neurons and cerebellar ataxia. These findings point to PARP1 as a possible therapeutic target in DNA strand break repair-defective disease.