Community Research and Development Information Service - CORDIS

Our understanding of the molecular mechanisms involved in the spreading, uptake, seeding, aggregation, of tau and alpha-synuclein and their impact on cell homeostasis, release and toxicity is still very sparse, hence limiting effective intervention strategies. A key objective of the action will be to use the recent advances in setting up both in vitro and in vivo model systems for spreading and seeding processes. Genome-wide genetic screens and small molecule screens to identify targets and mechanism involved in these processes should be performed. Based on the key mechanisms identified in these screens, targets will be chosen for further validation of drugabbility and therapeutic potential in vitro and in vivo.

In Alzheimer’s Disease (AD) extracellular depositions of amyloid beta peptides (plaques) and intracellular filamentous inclusions of tau (tangles) constitutes a hallmark of the disease. In Parkinson’s Disease (PD) the neuropathology is defined by intracellular inclusions of alpha-synuclein (Lewy bodies and Lewy neurites). Recently, new scientific opportunities to identify druggable targets have arisen based on the spreading and seeding hypothesis of tau and alpha-synuclein protein as prion-like proteins. This hypothesis allows setup of in vitro and in vivo models based on tau or alpha-synuclein pathological material isolated from patients, animal models or recombinant fibrils seeded into cells or animals and with a resulting defined mechanistic readout (spreading or seeding). Thus, it is envisioned that these models may be used in a screening setup to identify new targets and later validate their druggability. Advancing and focusing the research discoveries to identify drug targets related to Alzheimer’s and Parkinson’s disease requires multidisciplinary approaches including targets identification screens, tool compound development and validation in a wide range of experimental cell and animal disease models. The critical mass needed and availabilities of assay, models and reagents are only available through broad collaboration of public and private partners.

Several outputs from the project may contribute to the R&D process of developing new therapies against PD and AD. Establishing a common preclinical platform of assays based on the hypothesis of turnover / aggregation / spreading of misfolded pathological proteins is important to reach a consensus of how new treatment principles can best be evaluated and substantiated. Such a platform can form the basis for identification of new druggable targets which would open up for development of new innovative treatments against PD and AD.

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