Details

Autor(en) / Beteiligte

• Henderson, Michael X.
• Covell, Dustin J.
• Chung, Charlotte Hiu-Yan
• Pitkin, Rose M.
• Sandler, Raizel M.
• Decker, Samantha C.
• Riddle, Dawn M.
• Zhang, Bin
• Gathagan, Ronald J.
• James, Michael J.
• Trojanowski, John Q.
• Brunden, Kurt R.
• Lee, Virginia M.Y.
• Luk, Kelvin C.

Titel

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

Ist Teil von

• Neurobiology of disease, 2020-03, Vol.136, p.104712-104712, Article 104712

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2020

Quelle

Access via ScienceDirect (Elsevier)

Beschreibungen/Notizen

• 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 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 α-synuclein and show potent inhibition of pathology seeding in a neuronal model of α-synucleinopathy. A lead antibody was tested in a mouse model of PD, and it was able to reduce the spread of α-synuclein pathology in the brain and attenuate dopamine reductions in the striatum. This study highlights the therapeutic potential of α-synuclein immunotherapy for the treatment of PD and DLB, and provides a framework for screening of α-synuclein antibodies to identify those with preferred properties. •Conformation selective antibodies have less potential for off-target effects.•Inoculation of mice with misfolded α-synuclein generated a new class of antibodies.•Multi-assay screening identified highly selective and potent antibodies.•Lead antibody reduces α-synuclein pathology and improves dopamine in vivo.