Community Research and Development Information Service - CORDIS



Project ID: 337965
Funded under: FP7-IDEAS-ERC
Country: Switzerland

Mid-Term Report Summary - PROTEOTOXNET (Unraveling the cellular responses to aberrantly-folded and aggregated proteins)

Protein aggregation diseases such as Parkinson’s disease (PD) are associated with the intracellular accumulation of aggregates of specific aggregation-prone proteins (APPs). These structures have been associated to cellular toxicity and cell degeneration. Recent genetic screens and genome-wide association studies uncovered sets of genes that significantly reduce APP toxicity. These modulators are very promising for therapeutic purposes, but their mechanisms of action are currently unknown. To analyse the intracellular consequences of protein aggregation, we applied proteomics screens coupled with molecular biology follow-ups to a set of yeast and neuronal models of proteotoxicity, Our data suggest that intracellular responses depend on the sequence of the protein forming the aggregates and that APPs activate compartimentalized repsonses aimed at compensating for the aggregation insult. We also identified a novel cellular mechanism of clearance of pathological aggregates of alpha-synuclein (aSyn), a protein involved in PD, which counteracts its toxicity and pathological transcellular spread in vitro and in vivo. To evaluate the mechanism of action of genetic modifiers and risk factors of PD, we developed a novel mass spectrometric method, the sentinel assay, which relies on a set of marker proteins that cumulatively report on the activation state of ~200 biological processes. Last, we developed a novel structural proteomics approach (which we termed LiP-MS) to characterize pathological structural conversions of APPs directly in their cellular or tissue matrix and on a large-scale. We applied LiP-MS to characterize the structural features of pathological and physiological conformations of aSyn in various cell models of PD pathogenesis. The approach can be used to derive for the first time the in vivo structural properties of APP aggregates, but it finds also applications in the fields of drug target deconvolution, identification of novel allosteric interactions and biomarker discovery.

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