Alfa-synuklein patogenes - nya målmolekyler för terapi och diagnostik av Parkinsons sjukdom

Tidsperiod: 2012-01-01 till 2014-12-31

Projektledare: Martin Ingelsson

Medarbetare: Veronica Lindström, Hedvig Welander

Finansiär: Vetenskapsrådet

Bidragstyp: Projektbidrag

Budget: 1 500 000 SEK

Fibrillar alpha-synuclein in Lewy bodies is the main hallmark in brains of patients with Parkinson´s disease and some other brain disorders. However, recent studies indicate that oligomers or protofibrils of alpha-synuclein are more toxic to the brain than the ready-formed fibrils. We have developed in vitro protocols to generate stable alpha-synuclein oligomers, with a toxic impact on cultured cells. These protein forms have been used as antigens to raise monoclonal antibodies, which have been proven strongly selective for oligomers. In this project, we are now continuing our studies on the pathogenic mechanisms of alpha-synuclein oligomers. We are also applying the novel oligomer / protofibril-selective antibodies on brain tissue from patients and transgenic mice to detect prefibrillar alpha-synuclein pathology. Moreover, we will evaluate if our novel antibodies can be used for passive immunotherapy. So far, we have found that the antibodies can prevent alpha-synuclein oligomer formation on a cell model. We are now planning one study on 3-4 mos old mice, to investigate whether antibody treatment can prevent pathology, and one study on 10-12 mos old mice, to explore whether pathology can be reduced.Finally, we will assess whether patients with Lewy body pathology have altered plasma or cerebrospinal fluid levels of alpha-synuclein as compared to healthy controls. If so, oligomeric alpha-synuclein could potentially become a new biomarker for such disorders.