Cellular α -synuclein pathology is associated with bioenergetic dysfunction in Parkinson’s iPSC-derived dopamine neurons
Federico Zambon , Marta Cherubini , Hugo J R Fernandes , Charmaine Lang , Brent J Ryan , Viola Volpato , Nora Bengoa-Vergniory , Siv Vingill , Moustafa Attar , Heather D E Booth , Walther Haenseler , Jane Vowles , Rory Bowden , Caleb Webber , Sally A Cowley , Richard Wade-Martins
Using physiologically relevant iPSC-derived dopaminergic neurons (DAns) from PD patients carrying the A53T SNCA or the SNCA Tripl mutation this work addressed the cellular mechanisms associated with α synuclein in PD pathology. Detailed cell biological and transciptomics work revealed perturbations in the expression of genes linked to mitochondrial function together with increased endoplasmic reticulum stress and impairments in cholesterol and lipid homeostasis. This paper suggests that α Syn cellular pathology impacts cellular bioenergetics in dopamine neurons which may be the cause of cytotoxicity leading to cell loss of DAns in PD.