Project description
Epigenetics as a key driver of Parkinson’s disease
Epigenetic modifications such as methylation are well known to impact gene expression. Accumulating evidence indicates that N6-methyladenosine (m6A) methylation of eukaryotic RNAs serves as a post-transcriptional regulatory marker affecting splicing, translation and stability. Moreover, there has been a direct link with decreased m6A methylation and neuronal apoptosis. Funded by the Marie Skłodowska-Curie Actions programme, the PARTHECOM project aims to investigate how m6A regulates dopamine neuron survival and axonal regeneration. Researchers will identify which mRNAs with altered m6A methylation are responsible for dopamine neuron survival and test various small neuroprotective molecules. The work is expected to open new directions in research on Parkinson’s disease where dopamine neurons play a key role.
Objective
Parkinson’s disease (PD) is a neurodegenerative disease with growing incidence. More than 10 million people worldwide are affected by this condition. In addition to decline in the patients’ quality of life, the economic burden of PD is estimated to exceed 13,9 billion EUR in EU annually. Considering this, novel and more efficient therapeutic options are needed, as current PD treatments alleviate symptoms without stopping neurodegeneration and progression of the disease. Although the etiology of PD is unclear, degeneration of dopamine (DA) neurons has been shown to result from certain genetic mutations, toxins and pathological protein aggregation among others. Importantly, recent evidence points to decrease in mRNA methylation at adenosine N6 (m6A) in PD. Data also indicate that m6A reduction may induce DA neuron apoptosis.
Prof. Mart Saarma and collaborators have discovered that m6A methylation is a crucial regulator of neuronal apoptosis. They developed novel m6A methyltransferase activators and demethylase inhibitors that potently enhance mRNA m6A levels. Importantly, preliminary data show that these compounds protect DA neurons from neurotoxin-induced death in culture at nanomolar concentration. Moreover, one compound tested thus far remarkably improves motor behavior, protects and regenerates DA neurons and their axons in rat PD model more potently than “gold standard” GDNF. Considering this, the current project aims to elucidate the mechanisms how m6A regulates DA neuron survival and axonal regeneration. We will identify for the first time the mRNAs with increased/decreased methylation at adenosine N6 that regulate the life and death of DA neurons, thereby potentially opening new directions in PD research. In addition, we aim to provide completely new lead molecules for PD treatment.
In conclusion, the current project aims to broaden our understanding on the mechanisms of Parkinson’s disease and provide new drug candidates for novel PD therapeutic avenues.
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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
- natural sciences biological sciences biochemistry biomolecules proteins
- natural sciences biological sciences genetics mutation
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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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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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(opens in new window) HORIZON-MSCA-2021-PF-01
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00014 Helsinki
Finland
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