RNA-Binding Protein TDP 43 - Pathology in Aging
Nuclear loss or cytosolic aggregates of the RNA-binding protein TDP-43 are widely observed in the aging brain. They are a central hallmark of pathology in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD)1,2, but they are also observed in Alzheimer’s (AD) and other neurodegenerative diseases, as well as to a lesser degree during normal aging. Accordingly, it has been proposed that TDP-43 dysfunction or aggregation may be an important determinant of healthy vs. pathological aging, and that by influencing the degree of this TDP-43 dysfunction / aggregation, it may be possible to shift neuronal aging toward a healthier trajectory. A detailed understanding of the molecular mechanisms and cellular consequences of TDP-43 dysfunction and aggregation is therefore critical for identifying potential diagnostic and therapeutic strategies.
The project combines three objectives:
1. Impact of TDP-43 loss- or gain-of-function on synapse and circuit function in ‘humanized’ flies.
2. Cell type-specific consequences of TDP-43 loss- or gain-of-function on synapse and circuit function in mice.
3. Role of the deubiquitinase CYLD in regulating TDP-43 condensation / aggregation and resulting neuropathology
A key strength of this approach is that it bridges research fields across Mainz, linking the strong cell biology / biophysics research at JGU / IMB with the core neuroscience focus of the JGU and University Medical Center, as well as intertwining cell, fly and mouse research. In this manner, we extend the existing strength in research on condensation / proteostasis in cellular models by developing a new line of research in animal systems that will enable us to study the importance of protein condensation / aggregation in network function and behavior. This new direction provides a critical basis for the future development of diagnostic and therapeutic strategies based on targeting TDP-43 condensation / aggregation, with the aim of shifting cellular phenotypes from ‘pathological’ to ‘healthy’ and thereby promoting resilience to neuronal dysfunction in aging.
Principle Investigators
· Prof. Dr. Dilja Krueger-Burg, Institute of Anatomy, University Medicine, (person of contact email)
· Prof. Dr. Dorothee Dormann, Department of Molecular Cell Biology and Adjunct Director IMB
· Prof. Dr. Marion Silies, Institute of Developmental Biology and Neurobiology
· Prof. Dr. Dr. Michael Schmeißer, Institute of Anatomy, University Medicine
