Investigating Distinct Alpha Synuclein Oligomer‐Mediated Cellular Toxicity

Abstract

AbstractBackgroundAlpha Synuclein (ASyn), an amyloidogenic protein observed in Parkinson’s (PD) and Alzheimer’s (AD) disease, oligomers are toxic and polymorphic protein aggregates that with further investigation could be essential to improving potential neurodegenerative therapeutics.MethodUsing monoclonal antibodies (SynTCs) that bind toxic conformations of ASyn, we utilize cellular models such as primary cortical neurons and primary astrocytes isolated from C57/BL6 mice to investigate differences in the neurotoxic effects of ASyn oligomeric strains. These differences were evaluated by both immunocytochemistry and cell‐based assays. In addition, we analyzed the thermodynamic binding occurring between SynTCs and ASyn oligomeric strains.ResultUtilizing isothermal titration calorimetry (ITC), we confirm the thermodynamic binding between SynTCs and ASyn oligomers in contrast to ASyn monomers and fibrils. Asyn oligomeric strains exhibit differential toxicity in both primary neuron and astrocyte cells. When immunodepleted by SynTCs, cytotoxicity and endogenous ASyn aggregation decreased.ConclusionInvestigating mechanisms of neurotoxicity mediated by Asyn oligomeric strains is valuable in determining biological effects and the therapeutic potential of targeting and reducing toxic ASyn oligomers that contribute to the neurotoxicity observed in multiple neurodegenerative diseases.