LEAPSyn-SCI - Late Embryogenesis Abundant Proteins: Structural Characterisation and Interaction with α-Synuclein

Program for excellent projects of young researchers (PROMIS), Science Fund of the Republic of Serbia, 6039663, 2020-2022
Principal Investigator: Dr Marija Vidovic, IMGGE
Participant from IMGGE: Strahinja Stevanovic

The most common neurodegenerative disorders, Alzheimer’s and Parkinson's diseases, with high social costs, are tightly associated with the aggregation of intrinsically disordered protein α-Synuclein (α-Syn) into insoluble, amyloid fibrils. Despite numerous contemporary studies focused either on identifying small molecules that could interfere with the α-Syn aggregation or on immunotherapies towards amyloid fibrils, the cure for these diseases has not been found yet. A key objective for discovering the effective treatment is to understand the aggregation pathway of α-Syn and its normal and abnormal functions. The main idea of LEAPSyn-SCI is to develop a novel α-Syn anti-aggregation strategy employing the constituents of molecular mechanisms underlying the phenomenon of desiccation tolerance: Late Embryogenesis Abundant proteins (LEAPs), which may have role in stabilisation of the correct structure of proteins and membranes. The aim of LEAPSyn-SCI is to employ recombinantly produced LEAPs (originated from Arabidopsis thaliana – model plant and Ramonda serbica, ancient resurrection endemic plant) for stabilisation of aggregation-prone α-Syn. LEAPs from R. serbica are not identified so far. Obtained RsLEAP and AtLEAP will be structurally characterised in silico, as well as in vitro. Functional characterisation will include the elaboration of their potential to prevent protein aggregation and to ameliorate the effect of dehydration-induced damage of liposomes simulating biological membranes. Integrative in vitro and in silico analysis will be performed to understand the nature of the interactions between the LEAPs and α-Syn. Moreover, we will define the conditions which affect LEAPs/α-Syn interaction and aggregation pathway of α-Syn. Up to now, no LEAPs were applied for the inhibition of α-Syn aggregation. Evidence for α-Syn anti-aggregation activity of recombinant LEAPs provided by LEAPSyn-SCI will open up a novel approach for drug discovery strategies against Parkinson’s disease. Potential of LEAPs to stabilise proteins and membranes upon dehydration may be applied in biotechnology, pharmaceutical, food and cosmetic industry, cryopreservation and agriculture (new strategies for crops adaptation to arid climate).