Age-related neurodegeneration: From DNA damage to proteostasis loss, shifting the paradigm

• Applicant: Professor Dr. Björn Schumacher
• Subject Area: Biogerontology and Geriatric Medicine ; Experimental Models for the Understanding of Nervous System Diseases
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 540136447

The nuclear genome is under constant attack by endogenous and exogenous genotoxic sources. Various DNA repair deficiencies result in premature neurodegeneration in humans. The underlying role of DNA damage in promoting neuronal loss is currently being increasingly recognized as important, yet poorly understood causal factor for age-dependent neurodegeneration. Neurodegenerative disorders have remained a major clinical and societal challenge and due to their complexity effective therapeutic interventions have remained elusive. DNA damage gradually increases during aging and affects a wide range of homeostatic processes in the cell. The ensuing chronic DNA damage response (DDR) is thought to causally contribute to the aging process and drive the age-related degenerative pathologies. Here, we propose a highly innovative and complementary project that aims to provide new insight into the causal mechanisms of neurodegeneration. Prior and preliminary data of the Schumacher and Toiber labs have established that proteostatic processes are affected by DNA damage. Together, the two labs will combine their expertise on C. elegans and mammalian DDR. Schumacher has pioneered the investigation of organismal DDR in the nematode and will provide this genetically traceable in vivo model for DNA damage-driven and age-related neuronal degeneration. Toiber has uncovered mechanistic links between genome stability mechanisms and homeostatic alterations in the context of premature brain aging and neurodegeneration using the mammalian SIRT6 model. Based on their complementary data, the two groups will break new grounds in the understanding of the DNA damage-driven aging phenotype triggers the loss of protein homeostasis resulting in protein aggregation and subsequent neurodegeneration. To achieve this, we propose three specific aims that are only achievable through our close collaboration: We will (1) Identify the mechanistic links between DNA damage signaling and the regulation of proteostasis, (2) characterize how acute and chronic DNA damage signaling affects proteostasis robustness, and (3) delineate the role of proteostatic mechanisms in the cellular consequences of the acute and chronic DNA damage response in neurodegeneration. The high synergy between the experimental nematode and mammalian neurodegeneration systems combined with the assessment of the consequences of helix-distorting lesions and double strand breaks using the NER and SIRT6 models, respectively, allow generalizable conclusions that will provide new conceptual insights into the consequences of genome instability and causes of neurodegeneration.

• DFG Programme: Research Grants
• International Connection: Israel
• International Co-Applicant: Deborah Toiber, Ph.D.