Decoding the contribution of TDP-43 for synaptic failure in Alzheimer's Disease

Alzheimers Disease (AD) is an adult-onset disorder characterized by progressive neuronal loss and synaptic dysfunction, leading to severe cognitive decline. Nuclear loss and pathological inclusions of TDP-43 protein have been identified in 20-50% of AD patients, which associate with higher odds of cognitive decline, and faster brain atrophy rates. TDP-43 regulates RNA metabolism, and many of its RNA targets converge at synaptic function. Studies from me and others identified TDP-43 dependent mis-splicing in AD patients with TDP-43 pathology, strongly suggesting that TDP-43 loss-of-function is an important, yet understudied, pathway in AD. Here, I hypothesize that TDP-43 loss-of-function in AD leads to defects in its synaptic RNA targets, which in turn contribute to synaptic dysfunction and thus cognitive defects. I will use post-mortem tissue, induced pluripotent stem cells (iPSCs) and mouse models to characterize the impact of TDP-43 loss in synaptic function and composition, and matched these with RNA alterations resulting from TDP-43 loss-of-function. This will uncover novel synaptic signatures of TDP-43 dysfunction in AD, and offer new insights into neurodegeneration in AD. I will leverage my PhD training in synapse physiology and postdoctoral expertise in TDP-43 proteinopathy while working under the guidance of Dr. Ana Lusa Carvalho, a leading expert in synapse biology of disease. Dr. Carvalho is a dedicated mentor, and her lab at the Center for Neuroscience and Cell Biology (CNC) in Portugal is part of a top-tier research center with state-of-the-art facilities and a vibrant academic environment. This experience will be crucial for developing the scientific and transferable skills needed to achieve my goal of becoming an independent researcher within 2-3 years. I am enthusiastic about this opportunity and believe the MSCA postdoctoral fellowship would be transformative for my career and personal development.