Prion-like transmission of α-synuclein in Parkinson's disease

Obiettivo

Protein misfolding is implicated as a pathogenetic mechanism in several neurodegenerative disorders, including Parkinson¿s disease (PD). In prion disease, the misfolded protein spreads between cells and acts as a ¿permissive template¿, causing protein in the recipient cell to misfold. In 2008 we reported that classical neuropathological changes gradually propagate from a PD patient¿s brain to a graft of healthy neurons, over one decade after surgery. These groundbreaking findings suggest that the protein ¿-synuclei may transfer between cells and propagate protein aggregation in a ¿prion-like¿ fashion in PD. This molecular disease mechanism might explain how protein aggregates gradually spread throughout the nervous system and promote progression of disease symptoms. This highly novel concept represents a hitherto poorly explored route of intercellular communication and might have far-reaching implications well beyond PD. Little is known about how various forms of ¿-synuclein are taken up; if they seed aggregation in the recipient cell; how they affect proteostasis in the recipient cells; if they are transported axonally; and, finally, whether they can cause spreading of PD-like pathology in the nervous system.
In a multidisciplinary project will now examine the molecular mechanisms underlying translocation of ¿-synuclein across a lipid membrane, from the outside to the inside of a cell; what the molecular and functional consequences are of importing ¿-synuclein; what the dynamics of ¿-synuclein transfer are in vivo; whether aggregates of misfolded ¿-synuclein can spread from one region of the nervous system to another; what genes influence the likelihood for ¿-synuclein transfer to take place; and, finally if small molecules that inhibit ¿-synuclein can be identified. Our studies will shed light on what appears to be a new principle for pathogenesis of neurodegenerative disorders and can open up avenues for new therapeutic strategies.

Campo scientifico

Meccanismo di finanziamento

ERC-AG - ERC Advanced Grant

Istituzione ospitante

MAX IV Laboratory, Lund University

Contributo UE

€ 2 499 998,00

Indirizzo

Paradisgatan 5c
22100 LUND
Svezia

Regione

Södra Sverige Sydsverige Skåne län

Tipo di attività

Higher or Secondary Education Establishments

Ricercatore principale

Patrik Brundin (Prof.)

Contatto amministrativo

Diana Jerman (Ms.)

Collegamenti

Contatta l’organizzazione Sito web

Costo totale

Nessun dato

Beneficiari (1)