Project: Role and mechanism of alpha-synuclein and ataxin-3 spreading in Parkinson and Machado-Joseph diseases

Parkinson’s disease (PD) and Machado-Joseph Disease (MJD), are characterized by presence of pathogenic misfolded proteins, aggregates and inclusions. Recent advances suggest that both the spread of such proteins and impairments in autophagic clearance have a crucial importance for disease progression. Whether protein spreading is a neuron-autonomous process and contribution of other neural cell types has remained elusive. We hypothesize that exosome formation and autophagy intersect in a cross-disease pathway of key relevance for the spreading and accumulation of pathogenic proteins, in PD, MJD and potentially other neurodegenerative disorders. To investigate this hypothesis we will make use of PD- and MJD patient-derived induced pluripotent stem cells, which will be further utilized to derive disease-relevant neurons and astrocytes. These cell types will allow establishment of in vitro spreading assays and super-resolution imaging of aggregate, autophagosome and exosome dynamics. These in vitro approaches will be complemented by experiments addressing the in vivo graft-to-host propagation of protein aggregates. Finally, computational modeling of in vivo spreading will allow us to predict the routes of protein aggregate spread. This SynSpread project is expected to generate unique insights into the process of protein and aggregate spreading in PD and MJD, to development of novel in vitro and in vivo models and to unravelling of new targets for therapeutic intervention.

Acronym	SynSpread (Reference Number: JPND_CD_FP-688-031)
Duration	01/01/2015 - 01/01/2018
Project Topic	Neurodegenerative disease
Website	visit project website
Network	JPND
Call	A call for European research projects for cross-disease analysis of pathways related to neurodegenerative diseases

Project partner

Number	Name	Role	Country
1	University of Coimbra	Coordinator	Portugal
2	University of Luxembourg	Partner	Luxembourg
3	University Paris Descartes	Partner	France
4	University of Luxembourg	Partner	Luxembourg