Project: Pathway complexities of protein misfolding in neurodegenerative diseases: a novel approach to risks evaluation and model development

Acronym	REfrAME (Reference Number: 85)
Duration	01/09/2016 - 31/08/2019
Project Topic	The deposition of misfolded proteins in the central nervous system (CNS) of affected individuals is a common feature of major neurodegenerative disorders including Alzheimer’s disease (AD), Parkinson’s disease (PD), fronto-temporal dementias and prion diseases. Taken together, these diseases affect ~50 million people worldwide. AD, the most common form, is characterized by the cerebral deposition of aggregated amyloid β (Aβ) and tau, while PD is characterized by neuronal inclusions known as Lewy bodies that are comprised of the protein α-synuclein (α-syn). In prion diseases, the aggregated misfolded prion protein, called prion, is widespread in the CNS. A large body of histopathological, genetic, and experimental studies clearly implicates the conversion of native proteins into abnormal distinct conformations as a key step in the variegate disease pathogenesis. In this proposal we aim at studying the molecular determinants of the so-called strain phenomenon in the different diseases and relate the results to the functional and clinical outcome using several experimental tools. First, we plan to use small molecules to discriminate different structural conformers of Aβ, tau and α-syn. These molecules include luminescent conjugated oligothiophenes. In vitro and in vivo testing in cellular and animal models and human autopsy brains from clinically characterized disease cases will parallel biochemical and biophysical characterizations of such disease-related conformers. In addition, we propose the identification of genetic/epigenetic risk or protective factors through a high-throughput siRNA and RNSseq screenings for modifiers involved in the pathogenesis of these diseases. These latter two approaches will be paralleled by the study of the genes identified through in vitro and in vivo approaches for the development of novel experimental models for these diseases. The work plan proposed will address the genetic, epigenetic and environmental risk and protective factors and it will allow the development of novel advanced experimental models of neurodegenerative diseases. Overall the REfrAME consortium will work as unique and intertwined scientific environment in order to meet the challenges posed by the JPND call.
Network	JPco-fuND
Call	Neurodegenerative diseases: risk and protective factors, longitudinal cohort approaches and advanced experimental models

Project partner

Number	Name	Role	Country
1	Scuola Internazionale Superiore di Studi Avanzati-SISSA	Coordinator	Italy
2	Fondazione IRCCS Istituto Neurologico Carlo Besta	Partner	Italy
3	Deutsches Zentrum für Neurodegenerative Erkrankungen e.V. (German Center for Neurodegenerative Diseases, DZNE)	Partner	Germany
4	Medical Research Council	Partner	United Kingdom
5	Lund University	Partner	Sweden
6	University of Zurich (UZH)	Partner	Switzerland
7	Institute of Neuroimmunology, Slovak Academy of Sciences (SAS)	Partner	Slovakia