Cellular alpha-synuclein pathology is associated with bioenergetic dysfunction in Parkinson's iPSC-derived dopamine neurons

摘要

Parkinson's disease (PD) is the second most common neurodegenerative disorder and a central role for alpha-synuclein (alpha Syn; SNCA) in disease aetiology has been proposed based on genetics and neuropathology. To better understand the pathological mechanisms of alpha Syn, we generated induced pluripotent stem cells (iPSCs) from healthy individuals and PD patients carrying the A53T SNCA mutation or a triplication of the SNCA locus and differentiated them into dopaminergic neurons (DAns). iPSC-derived DAn from PD patients carrying either mutation showed increased intracellular alpha Syn accumulation, and DAns from patients carrying the SNCA triplication displayed oligomeric aSyn pathology and elevated alpha Syn extracellular release. Transcriptomic analysis of purified DAns revealed perturbations in expression of genes linked to mitochondrial function, consistent with observed reduction inmitochondrial respiration, impairment in mitochondrialmembrane potential, aberrant mitochondrial morphology and decreased levels of phosphorylated DRP1(Ser616). Parkinson's iPSC-derived DAns showed increased endoplasmic reticulum stress and impairments in cholesterol and lipid homeostasis. Together, these data show a correlation between alpha Syn cellular pathology and deficits in metabolic and cellular bioenergetics in the pathology of PD.