Curr Neurol Neurosci Rep (2012) 12:237–242 DOI 10.1007/s11910-012-0270-y GENETICS (V BONIFATI, SECTION EDITOR) Modeling Parkinson’s Disease Using Induced Pluripotent Stem Cells Blake Byers & Hsiao-lu Lee & Renee Reijo Pera Published online: 28 April 2012 # The Author(s) 2012. This article is published with open access at Springerlink.com Abstract Our understanding of the underlying molecular mechanism of Parkinson’s disease (PD) is hampered by a lack of access to affected human dopaminergic (DA) neurons on which to base experimental research. Fortunately, the recent development of a PD disease model using induced pluripotent stem cells (iPSCs) provides access to cell types that were previously unobtainable in sufficient quantity or quality, and presents exciting promises for the elucidation of PD etiology and the development of potential therapeutics. To more effec- tively model PD, we generated two patient-derived iPSC lines: a line carrying a homozygous p.G2019S mutation in the leucine-rich repeat kinase 2 (LRRK2) gene and another carrying a full gene triplication of the α-synuclein encoding gene, SNCA. We demonstrated that these PD-linked pluripo- tent lines were able to differentiate into DA neurons and that these neurons exhibited increased expression of key oxidative B. Byers : H.-l. Lee : R. Reijo Pera Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Palo Alto, CA, USA B. Byers e-mail: blakehbyers@gmail.com H.-l. Lee e-mail: hsiaolu@stanford.edu B. Byers Department of Bioengineering, Stanford University, Palo Alto, CA 94305, USA B. Byers Google Ventures, 1489 Charleston Road, Mountain View, CA 94043, USA H.-l. Lee : R. Reijo Pera (*) Department of Obstetrics and Gynecology, Stanford University, Stanford, CA, USA e-mail: reneer@stanford.edu stress response genes and α-synuclein protein. Moreover, when compared to wild-type DA neurons, LRRK2-G2019S iPSC-derived DA neurons were more sensitive to caspase-3 activation caused by exposure to hydrogen peroxide, MG- 132, and 6-hydroxydopamine. In addition, SNCA-triplication iPSC-derived DA neurons formed early ubiquitin-positive puncta and were more sensitive to peak toxicity from hydro- gen peroxide-induced stress. These aforementioned findings suggest that LRRK2-G2019S and SNCA-triplication iPSC- derived DA neurons exhibit early phenotypes linked to PD. Given the high penetrance of the homozygous LRRK2 muta- tion, the expression of wild-type α-synuclein protein in the SNCA-triplication line, and the clinical resemblance of patients afflicted with these familial disorders to sporadic PD patients, these iPSC-derived neurons may be unique and valuable models for disease diagnostics and development of novel pharmacological agents for alleviation of relevant disease phenotypes. Keywords Induced pluripotent stem cells . Parkinson’s disease . Disease modeling . Neurodegenerative disease . Development . Phenotype identification . α-Synuclein . Ubiquitin . Lewy bodies . Protein aggregation Introduction Neurodegenerative diseases are among the most intractable of human disorders. Over 100 years after Alois Alzheimer gave his first lecture on a patient with “a peculiar disorder of the cerebral cortex,” and almost 200 years since James Parkinson published his first description on the “shaking palsy,” we continue to search for the mechanisms that un- derlie the neurodegeneration in these eponymous diseases. Pathologically, the neurodegenerative disorders include Parkinson’s disease (PD), Alzheimer’s disease (AD), Hunting- ton’s disease, amyotrophic lateral sclerosis, frontotemporal