The use of patient-derived induced pluripotent stem cells (iPSCs) to study genetic mechanisms of disease has been limited by the confounding effect of genetic background. Now, Rudolf Jaenisch, Rajesh Ambasudhan, Stuart Lipton and colleagues report the use of isogenic iPSC-derived models of a dominant familial form of Parkinson's disease to study disease mechanisms (Cell 155, 1351–1364, 2013). The authors used previously generated human iPSCs from an individual with the coding mutation A53T in SNCA, which encodes α-synuclein, and an isogenic line in which this mutation was corrected in the endogenous α-synuclein locus using zinc-finger nuclease–mediated genome editing. The authors differentiated these cells into A9 dopaminergic neurons, the cell type affected in Parkinson's disease. They found that the A53T alteration caused increased amounts of α-synuclein protein aggregate, deficits in mitochondrial respiration and increased susceptibility to mitochondrial toxins. The authors determined that cells with the A53T alteration had increased reactive oxygen species and nitric oxide production, which disrupted a MEF2C-PGC1α–mediated neuroprotective pathway. The authors suggest that the MEF2C-PGC1α pathway may be a promising target for the development of therapeutics to treat Parkinson's disease.