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Project Topic
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Misfolding and aggregation of α-synuclein (α-syn) in the form of Lewy bodies and Lewy neurites are the neuropathological hallmarks of Parkinson’s disease (PD). Accumulating evidence shows that exogenous human α-syn fibrils originating from the PD patient brain, transgenic mouse brain or recombinantly synthetized from bacteria, can be taken up into neurons and stimulate aggregation of endogenous α-syn in cell models, or in laboratory animal models after injection into the brain or peripheral tissues. In this context, many fundamental questions still need to be answered in order to advance our understanding of the origin and the molecular mechanisms leading to the development of synucleinopathies and to design innovative protective strategies. For example, 1) when, why and how are the endogenous α-syn aggregates formed; do they initiate in the brain or in the gut and how do environmental factors, including the microbiome, contribute to this process; 2) what are the structural requirements for α-syn cell-to-cell propagation and spreading?; 3) how do the aggregation state and structural properties of the aggregates influence conversion of endogenous α-syn and pathology spreading?; 4) how, and through which route(s), is/are misfolded/aggregated α-syn transported and spread from one cell to another?; 5) how does genetic susceptibility, such as α-syn multiplications, parkin or GBA mutations, contribute to the propagation and aggregation of α-syn?; 6) how do posttranslational modifications of α-syn, such as phosphorylation and nitration, impact on α-syn spreading, aggregation and toxicity?; 7) can small molecule compounds and biological reagents, such as specific antibodies, block α-syn transfer, seeding and aggregation? This consortium is uniquely positioned to take advantage of combined cutting-edge technologies and complementary, multidisciplinary approaches and novel tools and capabilities developed in each of the participating groups, to address the above-mentioned important issues. These include expertise in unique capabilities in protein chemistry, biochemistry and biophysics, cell and molecular biology, generation of patient-derived iPS cells, microbiome analysis including functional metagenomic screening, wellestablished animal models (transgenic/knockout mice/rats and novel adeno-associated viral vectors) and imaging techniques including superresolution live cell imaging, and two-photon in vivo imaging. The fulfillment of this joint program will contribute significanlty to advancing our understanding of the interplay between genetic and environmental risk factors and their role in the initiation of α-syn aggregation and pathology spreading in PD and related synucleinopahties. A better understanding of the molecular, structural and cellular determinants underlying these processes will lead to the identification of novel targets and open new paths for the development of novel therapeutic preventive and therapeutic interventions. Moreover, it is highly likely that various misfolded proteins associated with other neurodegenerative diseases may be propagated through similar mechanisms. Therefore, we anticipate that our findings may also be generally applicable to other neurodegenerative diseases.
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