Research ArticleParkinson’s Disease

Pharmacological Rescue of Mitochondrial Deficits in iPSC-Derived Neural Cells from Patients with Familial Parkinson’s Disease

Science Translational Medicine  04 Jul 2012:
Vol. 4, Issue 141, pp. 141ra90
DOI: 10.1126/scitranslmed.3003985

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Understanding Mitochondrial Deficits in Parkinson’s Disease

Parkinson’s disease (PD) is a common, progressive neurodegenerative disease characterized by loss of dopaminergic neurons in the nigrostriatal pathway of the brain, resulting in motor and cognitive deficits. Rodent and primate models only partially predict disease mechanisms. In a new study, Cooper et al. set out to make a human cellular model of PD. First, the authors obtained fibroblasts from members of families with genetically defined forms of PD and generated induced pluripotent stem cells (iPSCs) from the fibroblasts. They then induced differentiation of these PD patient–derived iPSCs into neural cells including dopaminergic neurons to study how the genetic mutations influenced the responses of neural cells to various cellular stressors. Mitochondrial dysfunction has already been implicated in the pathogenesis of PD, so the authors decided to treat their iPSC-derived neural cells from patients with rare familial forms of PD with chemical stressors and toxins known to disrupt mitochondrial function. The researchers observed a gradual increase in sensitivity to cellular stress as the cell type analyzed became functionally closer to the vulnerable cell types in the PD brain; that is, fibroblasts taken directly from PD patients were less sensitive to the chemical stressors than iPSC-derived neural cells. Several drugs helped iPSC-derived neural cells to resist the damaging effects of the cellular stressors. These studies with human neural cells from iPSCs from patients with familial PD highlight opportunities to characterize disease pathways and to screen for new therapeutic agents.