Project description
Unveiling the prion-like nature of Parkinson's disease: a paradigm shift
The uncontrollable movement associated with Parkinson’s disease (PD) is a result of chronic neural degeneration. One of the hallmarks of PD pathophysiology is the accumulation of aggregates of the alpha synuclein (AS) protein. Funded by the Marie Skłodowska-Curie Actions programme, the Alpha-Synuclein project is working under the hypothesis that AS behaves like a prion, spreading from the peripheral nervous system to the central nervous system, which exacerbates oxidative stress and dysfunction and leads to loss of neurons in the brain. To prevent this neurotoxicity and degeneration, researchers suggest creating a new model to study AS propagation, focusing on the role of specific genes in AS spreading and toxicity.
Objective
A prion-like behavior of α-synuclein (AS) protein has been hypothesized in the pathogenesis of Parkinson disease (PD). According to this hypothesis, pathogenic forms “seeds” of AS propagate from periphery into the neurons of central nervous system (CNS), where they recruit endogenous AS in the first receiving neurons, exit the cell and enter connected neurons. The ongoing AS aggregation and cell-cell propagation is considered to induce oxidative stress, neuronal dysfunction and neuronal loss in CNS. Therefore, blocking the neuronal propagation of AS will prevent AS neurotoxicity and neurodegeneration. I propose to develop and validate a novel in vivo model of prion-like AS propagation, in which I will selectively modify the genetic makeup of first receiving neurons, and use this model for mechanistic investigations. I will use a transgenic M83 mouse model overexpressing mutant A53T human AS in which prion-like spreading is initiated by injecting preformed AS aggregates into the hindlimb musculus femoris. These AS aggregates are taken up by sensory and/or motor nerve endings in the muscle, are retrogradely transported through the sciatic nerve into spinal cord, and rostrally into the brainstem and higher brain areas over time. I will refine this model by transducing the sciatic nerve endings with intramuscular delivery of rAAV viral vectors- containing novel CRISPR/Cas9 genome editing tools targeting genes of interest- to prevent in vivo prion-like AS spreading and/or toxicity. As proof of concept, I will silence AS in the receiving neurons to demonstrate this slows the disease development in the model. Once validated, I will use the model for hypothesis-driven mechanistic investigations of candidate genes, which initially include: 1) ubiquitin specific peptidase 19 (USP19)- since it has been implicated in cellular excretion of misfolded AS in vitro, and 2) eukaryotic elongation factor-2 kinase (eEF2K)- since it is abnormally activated in postmortem PD brain tissue.
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 medical biotechnology genetic engineering gene therapy
- natural sciences biological sciences biochemistry biomolecules proteins
- medical and health sciences basic medicine neurology neurodegenerative diseases parkinson
- natural sciences biological sciences genetics genomes
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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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H2020-EU.1.3. - EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions
MAIN PROGRAMME
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H2020-EU.1.3.2. - Nurturing excellence by means of cross-border and cross-sector mobility
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Topic(s)
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.
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.
Funding Scheme
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.
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.
MSCA-IF-EF-ST - Standard EF
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Call for proposal
Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.
Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.
(opens in new window) H2020-MSCA-IF-2017
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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.
8000 Aarhus C
Denmark
The total costs incurred by this organisation to participate in the project, including direct and indirect costs. This amount is a subset of the overall project budget.