Characterization of novel conformation-selective alpha-synuclein antibodies as potential immunotherapeutic agents for Parkinson's disease

Parkinson's disease (PD) and dementia with Lewy bodies (DLB) are progressive neurodegenerative diseases for which there is no disease-modifying treatment. PD and DLB are characterized by aggregation of the synaptic protein alpha-synuclein, and there is compelling evidence to suggest that progression of these diseases is associated with the trans-cellular spread of pathogenic alpha-synuclein through the brains of afflicted individuals. Therapies targeting extracellular, pathogenic alpha-synuclein may therefore hold promise for slowing or halting disease progression. In this regard, it has been suggested that highly-selective antibodies can be administered as therapeutic agents targeting pathogenic proteins. In the current study, we screened a series of antibodies using multiple selection criterion to identify those that selectively bind pathogenic alpha-synuclein and show potent inhibition of pathology seeding in a neuronal model of alpha-synucleinopathy. A lead antibody was tested in a mouse model of PD, and it was able to reduce the spread of alpha-synuclein pathology in the brain and attenuate dopamine reductions in the striatum. This study highlights the therapeutic potential of alpha-synuclein immunotherapy for the treatment of PD and DLB, and provides a framework for screening of alpha-synuclein antibodies to identify those with preferred properties.