Objective
Mutations in Presenilin 1 (PSEN1) represent the most common cause of autosomal dominant familial Alzheimer’s disease (fAD), resulting in a severe early-onset phenotype. Two pathogenic PSEN1 variants, the intron 4 deletion (int4del) and the missense mutation R278I, have been associated with fAD. However, their transcriptional consequences remain remarkably understudied.
I hypothesise that int4del and R278I (i) perturb PSEN1 splicing, thereby compromising diverse PSEN1 functions in neuronal pathways that are central to Alzheimer’s pathogenesis, with the potential to exacerbate pathology; and (ii) can reveal molecular mechanisms shared with sporadic forms of the disease, paving the way for novel therapeutic strategies.
To test this hypothesis, I propose analysing a novel long-read RNA-sequencing dataset formed by 12 induced pluripotent stem cell (iPSC)-derived samples from two fAD patients. These include triplicate neuronal lines harbouring the int4del and R278I mutations, respectively, alongside isogenic CRISPR-Cas9-corrected controls. Using cutting-edge techniques developed at Prof. Ana Conesa’s lab (I2SysBio, Valencia, Spain), I will: (i) characterise the complex transcriptional landscape associated with each mutation; (ii) predict the disruption of cis-acting regulators and related consequences on transcript structure; (iii) evaluate downstream cellular pathways compromised by altered transcripts; and (iv) cross-evaluate the fAD transcriptional signatures detected against published datasets from sporadic AD (sAD) patients. During my secondment at the Institute of Neurosciences (Alicante, Spain), I will be excellently trained in wet-lab assays to acquire practical skills in shRNA delivery and cell line manipulation within the context of neurodegeneration.
This work will provide critical insights into the transcriptional mechanisms underlying fAD pathogenesis, aiming to inform the identification of novel RNA therapeutic strategies with applications in sAD.
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 physiology pathophysiology
- medical and health sciences medical biotechnology cells technologies stem cells
- natural sciences biological sciences genetics mutation
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Programme(s)
Multi-annual funding programmes that define the EU’s priorities for research and innovation.
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-2025-PF
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Net EU financial contribution. The sum of money that the participant receives, deducted by the EU contribution to its linked third party. It considers the distribution of the EU financial contribution between direct beneficiaries of the project and other types of participants, like third-party participants.
28006 MADRID
Spain
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