Project: Unravelling the pathophysiological role of alpha-synuclein aggregation, transmission and neuroinflammation in neurodegeneration

Acronym	SYNACTION (Reference Number: 63)
Duration	01/03/2016 - 28/02/2019
Project Topic	Misfolded protein aggregates are a common feature of several ageing-related neurodegenerative diseases. Although the major protein component and the affected brain regions are different for each neurodegenerative disease, (e.g. α-synuclein (αSYN) in Parkinson‟s disease (PD), amyloid-β (Aβ)/Tau in Alzheimer‟s disease (AD) and huntingtin (htt) in Huntington‟s disease (HD)), several proteins misfold and accumulate in multiple diseases. The discovery of the prion-like transmissible nature of amyloidogenic proteins suggests a pathogenic trigger which might propagate throughout the nervous system driving the progression of the disease (Hansen 2011). The molecular hallmark of synucleinopathies such as PD, dementia with Lewy bodies (DLB) and multiple system atrophy (MSA) are megadalton αSYN-rich deposits suggestive of one molecular event causing distinct disease phenotypes. We recently observed that αSYN assemblies with different structural characteristics or „strains‟ display distinct spreading, tropism, clearance and neurotoxicity in cells and in the rodent brain (Bousset 2013; Peelaerts 2015). Strain-specific pathology was induced resembling pathological hallmarks found in PD and MSA patients. We therefore hypothesize that distinct phenotypes in synucleinopathies might correlate to heterogeneity in αSYN strains in patients. We also postulate that neuroinflammatory processes are linked to αSYN transmission and neurotoxicity. In this project, we will study the relationship between αSYN transmission, neurotoxicity and neuroinflammation using state-of-the-art advanced experimental rodent and non-human primate models. The αSYN assemblies will be made de novo in vitro or purified and amplified from human brain samples of PD, MSA and DLB patients. Samples of both sexes will be represented. Readouts will include behavioural, imaging, biochemical and histochemical analysis of αSYN assemblies, aggregation and propagation of the induced lesions in the brain and affected areas. Furthermore, we will study the involvement of the innate and adaptive immune system by investigating the activation of microglia and the infiltration of peripheral leukocytes (myeloid and T cells) following the injection of different αSYN assemblies in the brain. A better understanding of the role of intercellular transmission and neuroinflammation in αSYN-linked neurodegeneration will contribute to early diagnosis, prevention and the development of novel therapeutic strategies for synucleinopathies and other ageing-related disorders.
Network	JPco-fuND
Call	Neurodegenerative diseases: risk and protective factors, longitudinal cohort approaches and advanced experimental models

Project partner

Number	Name	Role	Country
1	KATHOLIEKE UNIVERSITEIT LEUVEN	Coordinator	Belgium
2	CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE	Partner	France
3	UNIVERSITAETSKLINIKUM BONN	Partner	Germany
4	INSTITUT DU CERVEAU ET DE LA MOELLE EPINIERE	Partner	France