title: LRRK2 mutant iPSC-derived DA neurons demonstrate increased susceptibility to oxidative stress.
abstract: Studies of Parkinson's disease (PD) have been hindered by lack of access to affected human dopaminergic (DA) neurons. Here, we report generation of induced pluripotent stem cells that carry the p.G2019S mutation (G2019S-iPSCs) in the Leucine-Rich Repeat Kinase-2 (LRRK2) gene, the most common PD-related mutation, and their differentiation into DA neurons. The high penetrance of the LRRK2 mutation and its clinical resemblance to sporadic PD suggest that these cells could provide a valuable platform for disease analysis and drug development. We found that DA neurons derived from G2019S-iPSCs showed increased expression of key oxidative stress-response genes and α-synuclein protein. The mutant neurons were also more sensitive to caspase-3 activation and cell death caused by exposure to stress agents, such as hydrogen peroxide, MG-132, and 6-hydroxydopamine, than control DA neurons. This enhanced stress sensitivity is consistent with existing understanding of early PD phenotypes and represents a potential therapeutic target.
authors.affiliation: Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA 94305, USA.
authors.forename: Ha Nam
authors.initials: HN
authors.lastname: Nguyen
authors.forename: Blake
authors.initials: B
authors.lastname: Byers
authors.forename: Branden
authors.initials: B
authors.lastname: Cord
authors.forename: Aleksandr
authors.initials: A
authors.lastname: Shcheglovitov
authors.forename: James
authors.initials: J
authors.lastname: Byrne
authors.forename: Prachi
authors.initials: P
authors.lastname: Gujar
authors.forename: Kehkooi
authors.initials: K
authors.lastname: Kee
authors.forename: Birgitt
authors.initials: B
authors.lastname: Schüle
authors.forename: Ricardo E
authors.initials: RE
authors.lastname: Dolmetsch
authors.forename: William
authors.initials: W
authors.lastname: Langston
authors.forename: Theo D
authors.initials: TD
authors.lastname: Palmer
authors.forename: Renee Reijo
authors.initials: RR
authors.lastname: Pera
mesh_terms: D000577:Amides / Q000494:pharmacology; D019943:Amino Acid Substitution / Q000187:drug effects; D000818:Animals; D016923:Cell Death / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D004298:Dopamine / Q000378:metabolism*; D005260:Female; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D057026:Induced Pluripotent Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D007976:Leupeptins / Q000494:pharmacology; D008636:Mesencephalon / Q000473:pathology; D051379:Mice; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009474:Neurons / Q000187:drug effects / Q000473:pathology*; D018384:Oxidative Stress / Q000187:drug effects; D016627:Oxidopamine / Q000494:pharmacology; D010300:Parkinson Disease / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D010641:Phenotype; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D000577:Amides; D007976:Leupeptins; D011725:Pyridines; C108830:Y 27632; D016627:Oxidopamine; D006861:Hydrogen Peroxide; C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde; D004298:Dopamine