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The Role of Complex I Assembly Factors during Prion Diseases: Insights into Mitochondrial Neurobiology

Objective

Mitochondria have a crucial role in cell survival and apoptosis, in particular in long-lived cells such as neurons. Mitochondria generate energetic potential through respiratory complexes I to IV, which constitute the electron transport chain. A number of studies demonstrates that mitochondrial integrity declines as a function of aging and dysfunctions may be exacerbated by age-related neurodegenerative diseases. Altered levels of complex I proteins have been found to be directly responsible for a decrease in energy production in Alzheimer’s and Parkinson's disease. Recently, a number of nuclear encoded mitochondrial proteins, denoted as “assembly factors” (AFs), have been identified as crucial components helping the complex I assembly. Defects in AFs (due to mutations or aberrant AFs processing) may cause complex I misassembly and mitochondrial dysfunctions leading to a broad spectrum of diseases, including neurological disorders in childhood-related dieseas as Leigh syndrome. The functional role of AFs during neurodegeneration has not been investigated yet. With the “Prion Respiration” project I propose to develop a research approach aimed at the identification of the biological role of three crucial complex I AFs (namely ECSIT, NDUFAF1 and ACAD9) in cellular and animal models using prion diseases as robust system to study neurodegenerative diseases. Subsequently, the role of prions in interfering the with the correct assembly of the AFs will be investigated using structural biology approaches, as SAXS and cryo-EM methods. The structural and functional characterization of key proteins involved in mitochondrial respiration will provide insights into the underlying mechanisms involved in neuronal function and may represent novel targets for structure-based drug design strategies to prevent or diminish the oxidative stresses underlying neurodegeneration.

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Keywords

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Programme(s)

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Topic(s)

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Funding Scheme

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MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)

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Call for proposal

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(opens in new window) H2020-MSCA-IF-2018

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Coordinator

UNIVERSITA DEGLI STUDI DI TRENTO
Net EU contribution

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.

€ 171 473,28
Address
VIA CALEPINA 14
38122 Trento
Italy

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Region
Nord-Est Provincia Autonoma di Trento Trento
Activity type
Higher or Secondary Education Establishments
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Total cost

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.

€ 171 473,28
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