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Characterization of pathology-inducing α-synuclein species from human diseased brain tissue

John D. Graef, Nina Hoque, Craig Polson, Ling Yang, Lawrence Iben, Yang Cao, Nino Devidze, Michael K. Ahlijanian, Jere E. Meredith Jr.
doi: https://doi.org/10.1101/588335
John D. Graef
Genetically-Defined Diseases, Bristol-Myers Squibb Company, Wallingford CT, USA
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Nina Hoque
Genetically-Defined Diseases, Bristol-Myers Squibb Company, Wallingford CT, USA
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Craig Polson
Genetically-Defined Diseases, Bristol-Myers Squibb Company, Wallingford CT, USA
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Ling Yang
Genetically-Defined Diseases, Bristol-Myers Squibb Company, Wallingford CT, USA
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Lawrence Iben
Genetically-Defined Diseases, Bristol-Myers Squibb Company, Wallingford CT, USA
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Yang Cao
Genetically-Defined Diseases, Bristol-Myers Squibb Company, Wallingford CT, USA
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Nino Devidze
Genetically-Defined Diseases, Bristol-Myers Squibb Company, Wallingford CT, USA
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Michael K. Ahlijanian
Genetically-Defined Diseases, Bristol-Myers Squibb Company, Wallingford CT, USA
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  • For correspondence: mpenahl@yahoo.com
Jere E. Meredith
Genetically-Defined Diseases, Bristol-Myers Squibb Company, Wallingford CT, USA
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Abstract

Synucleinopathies are a group of neurodegenerative diseases characterized by the presence of pathological accumulations of misfolded, phosphorylated α-synuclein (αSyn) protein. Multiple lines of evidence indicate that synucleinopathy disease progression is driven by a prion-like process of transmission of a pathologic form of αSyn. One potential therapeutic approach to prevent cell-to-cell propagation is to target this transmissible species with selective antibodies. In this study, a rodent primary neuronal culture reporter system was developed to monitor induction of detergent-insoluble, phosphorylated (pS129) aggregates of αSyn. Induction of pS129 αSyn pathology was observed with both synthetic αSyn fibrils (PFFs) and brain lysates from multiple system atrophy (MSA) patients but not αSyn monomers or human brain lysate controls. The induction-competent species in MSA lysates could be enriched by high-speed centrifugation suggesting that it is present as a high molecular weight aggregate. Furthermore, samples derived from brain lysates from Parkinson’s disease (PD) and Dementia with Lewy Bodies (DLB) patients also induced pS129 αSyn pathology, but required longer incubation times. Lastly, the potential of αSyn selective antibodies to immunodeplete induction-competent forms of αSyn from both PFF and synucleinopathy brain samples is described. The results demonstrate that antibodies targeting the C-terminal of αSyn are most effective for immunodepletion of pathology-inducing forms of αSyn from samples derived from human synucleinopathy brains. Furthermore, the data support the hypothesis that antibodies that recognize a C-terminal epitope and exhibit selectivity for oligomeric forms over monomeric forms of αSyn represent a desirable target for immunotherapy for synucleinopathy patients.

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Posted March 25, 2019.
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Characterization of pathology-inducing α-synuclein species from human diseased brain tissue
John D. Graef, Nina Hoque, Craig Polson, Ling Yang, Lawrence Iben, Yang Cao, Nino Devidze, Michael K. Ahlijanian, Jere E. Meredith Jr.
bioRxiv 588335; doi: https://doi.org/10.1101/588335
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Characterization of pathology-inducing α-synuclein species from human diseased brain tissue
John D. Graef, Nina Hoque, Craig Polson, Ling Yang, Lawrence Iben, Yang Cao, Nino Devidze, Michael K. Ahlijanian, Jere E. Meredith Jr.
bioRxiv 588335; doi: https://doi.org/10.1101/588335

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