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NeuroInCellNMR Report Summary

Project ID: 647474
Funded under: H2020-EU.1.1.

Periodic Reporting for period 1 - NeuroInCellNMR (In-cell NMR monitoring of alpha-Synuclein aggregation in neuronal cells)

Reporting period: 2015-11-01 to 2017-04-30

Summary of the context and overall objectives of the project

The goal of the NeuroInCellNMR project is to derive atomic-resolution information about the structural states of human alpha-synuclein in the course of amyloid formation in neuronal and non-neuronal cells. Intracellular aggregation of alpha-synuclein is causally linked to Parkinson’s disease, the second most common neurodegenerative disorder in humans. Overall objectives of our research are to delineate novel insights into the conformational rearrangements that initiate and propagate alpha-synuclein aggregation in the course of Parkinson’s disease.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

So far, we delineated a first set of full-scale, atomic-resolution descriptions of intracellular alpha-synuclein structures in five different mammalian cell types under physiological conditions (Nature, 2016). We further analyzed the capacity of healthy mammalian cells to repair oxidative alpha-synuclein damage in a site-selective and stepwise manner (Nat Commun, 2016). We developed a novel procedure to determine in-cell protein structures from simple 2D NMR experiments (J Phys Chem Lett, 2016) and applied this tool to resolve the stepwise phosphorylation behavior of a related, disordered protein region (Science, 2016). We identified a novel biological activity of human alpha-synculein regarding its ability to interact with endogenous cellular membranes, which serves as the basis for ongoing experiments addressing its aggregation propensity at membrane interfaces.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

At this point, we are making good progress in deciphering previously unknown biological scenarios that precede intracellular aggregation. We are confident that these will allow us to design better pharmacological strategies to inhibit alpha-synuclein aggregation and the onset of Parkinson’s disease.

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