Project description
Molecular insight into Alzheimer’s synaptic dysfunction
TDP-43 is an RNA-binding protein that regulates RNA processing, transport, stability and translation of genes involved in synaptic function. TDP-43 is lost from the nucleus and forms abnormal inclusions in the brain in about half of patients with Alzheimer’s disease (AD). Although such TDP-43 dysfunction is linked to faster brain degeneration and greater cognitive decline, the underlying mechanism remains poorly understood. With the support of the Marie Skłodowska-Curie Actions programme, the SynTDP project will investigate how TDP-43 loss contributes to synaptic dysfunction in AD. Researchers will utilise post-mortem brain tissue and mouse models to reveal synaptic RNA and protein changes caused by TDP-43 loss. Findings could reveal new therapeutic targets for slowing AD progression.
Objective
Alzheimer’s 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 Luísa 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.
Fields of science (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
- natural sciences biological sciences neurobiology
- medical and health sciences basic medicine neurology dementia alzheimer
- medical and health sciences basic medicine pathology
- medical and health sciences basic medicine physiology
- natural sciences biological sciences genetics RNA
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Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
Programme(s)
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Multi-annual funding programmes that define the EU’s priorities for research and innovation.
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HORIZON.1.2 - Marie Skłodowska-Curie Actions (MSCA)
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Calls for proposals are divided into topics. A topic defines a specific subject or area for which applicants can submit proposals. The description of a topic comprises its specific scope and the expected impact of the funded project.
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Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
HORIZON-TMA-MSCA-PF-EF - HORIZON TMA MSCA Postdoctoral Fellowships - European Fellowships
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Call for proposal
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(opens in new window) HORIZON-MSCA-2024-PF-01
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3004-531 Coimbra
Portugal
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