Gene-corrected Parkinson's disease neurons show the A30P alpha-synuclein point mutation leads to reduced neuronal branching and function

Barbuti, P. A.; Santos, B. F.; Antony, P. M.; Massart, F.; Cruciani, G.; Dording, C. M.; Pavelka, L.; Kwon, Y.-J.; Krueger, R. A.

doi:10.1101/2020.11.05.369389

bioRxiv · 10.1101/2020.11.05.369389

Gene-corrected Parkinson's disease neurons show the A30P alpha-synuclein point mutation leads to reduced neuronal branching and function

Barbuti, P. A.·Santos, B. F.·Antony, P. M.·Massart, F.·Cruciani, G.·Dording, C. M.·Pavelka, L.·Kwon, Y.-J.·Krueger, R. A.

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Abstract

Parkinsons disease is characterised by the degeneration of A9 dopaminergic neurons and the pathological accumulation of alpha-synuclein. In a patient-derived stem cell model, we have generated dopaminergic neurons from an individual harbouring the p.A30P SNCA mutation and compared those neurons against gene-corrected isogenic control cell lines. We have used confocal microscopy to assess the neuronal network, specifically segmenting dopaminergic neurons and have identified image-based phenotypes showing axonal impairment and reduced neurite branching. We show using multi-electrode array (MEA) technology that the neurons carrying the endogenous p.A30P alpha-synuclein mutation are functionally impaired and identified mitochondrial dysfunction as a pathogenic cellular phenotype. We report that against gene-corrected isogenic control cell lines the neurons carrying the p.A30P SNCA mutation have a deficit and are susceptible to the mitochondrial toxin and environmental pesticide Rotenone. Our data supports the use of isogenic cell lines in identifying image-based pathological phenotypes that can serve as an entry point for future disease modifying compound screenings and drug discovery strategies.

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Barbuti, P. A., Santos, B. F., Antony, P. M., Massart, F., Cruciani, G., Dording, C. M., Pavelka, L., Kwon, Y.-J., Krueger, R. A.. 2020-11-06. Gene-corrected Parkinson's disease neurons show the A30P alpha-synuclein point mutation leads to reduced neuronal branching and function. https://doi.org/10.1101/2020.11.05.369389

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