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


ABSTRACT: 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 ?-synuclein, and there is compelling evidence to suggest that progression of these diseases is associated with the trans-cellular spread of pathogenic ?-synuclein through the brains of afflicted individuals. Therapies targeting extracellular, pathogenic ?-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 ?-synuclein and show potent inhibition of pathology seeding in a neuronal model of ?-synucleinopathy. A lead antibody was tested in a mouse model of PD, and it was able to reduce the spread of ?-synuclein pathology in the brain and attenuate dopamine reductions in the striatum. This study highlights the therapeutic potential of ?-synuclein immunotherapy for the treatment of PD and DLB, and provides a framework for screening of ?-synuclein antibodies to identify those with preferred properties.

SUBMITTER: Henderson MX 

PROVIDER: S-EPMC7026836 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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

Henderson Michael X MX   Covell Dustin J DJ   Chung Charlotte Hiu-Yan CH   Pitkin Rose M RM   Sandler Raizel M RM   Decker Samantha C SC   Riddle Dawn M DM   Zhang Bin B   Gathagan Ronald J RJ   James Michael J MJ   Trojanowski John Q JQ   Brunden Kurt R KR   Lee Virginia M Y VMY   Luk Kelvin C KC  

Neurobiology of disease 20191216


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 α-synuclein, and there is compelling evidence to suggest that progression of these diseases is associated with the trans-cellular spread of pathogenic α-synuclein through the brains of afflicted individuals. Therapies targeting extracellular, pathogenic α-synuclein may therefo  ...[more]

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