DNA Damage Signaling to Mitochondrial Dysfunction in Neurodegeneration and Aging

We find that some DNA repair defective diseases with severe neurodegeneration have mitochondrial dysfunctiuon. Our studies involve cell lines, the worm (c.elegans), and mouse models and include the premature aging syndromes Xeroderma pigmentosum group A, Cockaynes syndrome, Ataxia telangiectasia and Werner syndrome. We find a pattern of hyperparylation, deficiency in the NAD+and Sirtuin signaling and mitochondrial stress. We are pursuing mechanistic studies of this signaling and interventions at different steps to improve mitochondrial health and the neurodegeneration. I will discuss intervention studies in these diseases models including a new Alzheimer mouse model using NAD supplementation. NAD supplementation stimulates mitochondrial functions including mitophagy and stimulates DNA repair pathways. Based on human postmortem material and IPSC cells we identify mitophagy defects as a prominent feature in Alzheimers disease (AD). Using c.elegans AD models we screened for mtophagy stimulators and identified compounds that subsequentially also show major improvement of AD features in mouse models.