DNA repair dysfunction in neurodegeneration

National Institute On Aging

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Abstract

Our goal here is to determine whether changes in the formation or processing of oxidative DNA damage are associated with neurodegeneration. It is our hypothesis that DNA repair systems play critical roles in responding to multiple types of acute and chronic cellular stress. We have identified a DNA damage response cascade leading from PARP1 to defected mitophagy. In the rare autosomal recessive disease Ataxia Telangiectasia (AT,) we documented increased PARylation, low NAD+ and mitochondrial dysfunction across multiple species. Importantly, treatment with NAD+ precursors that restored NAD levels reduced the severity of AT neuropathology, improved neuromuscular function, delayed memory loss and dramatically extended lifespan. Mechanistically, we ascribed the benefits to improvements in DNA repair and mitophagy. This work underscores the important linkage between DNA repair and mitochondrial function and further points to novel therapeutic interventions.