DNA repair dysfunction in neurodegeneration and Alzheimer's Disease

National Institute On Aging

Investigators

Linked publications, trials & patents

Abstract

Our goal here is to determine whether changes in the formation or processing of oxidative DNA damage are associated with neurodegeneration and Alzheimers Disease (AD). 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 parylation to defective mitophagy. In the rare autosomal recessive disease Ataxia Telangiectasia (A-T,) 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 A-T neuropathology, improved neuromuscular function, delayed memory loss, and dramatically extended lifespan. Mechanistically, we ascribed the benefits to improvements in DNA repair and mitophagy. However, upon further investigation we also came to know that NR, nicotinamide riboside, which is an NAD+ supplement, can prevent senescence and SASP, senescence associated secretory phenotype. We demonstrate that NR can suppress senescence and cGAS/STING activation by promoting mitophagy in a PINK1-dependent manner. NR also improved motor function in Atm-null mice. This work underscores the important linkage between DNA repair and mitochondrial function and further points towards possible novel therapeutic interventions for A-T. Our research also suggests a central role for mitochondrial dysfunction-induced senescence in A-T pathogenesis. We are continuing to explore the potential utility of NR for DNA repair-deficient disorders and in age-related diseases.