title: Identification and rescue of α-synuclein toxicity in Parkinson patient-derived neurons.
abstract: The induced pluripotent stem (iPS) cell field holds promise for in vitro disease modeling. However, identifying innate cellular pathologies, particularly for age-related neurodegenerative diseases, has been challenging. Here, we exploited mutation correction of iPS cells and conserved proteotoxic mechanisms from yeast to humans to discover and reverse phenotypic responses to α-synuclein (αsyn), a key protein involved in Parkinson's disease (PD). We generated cortical neurons from iPS cells of patients harboring αsyn mutations, who are at high risk of developing PD dementia. Genetic modifiers from unbiased screens in a yeast model of αsyn toxicity led to identification of early pathogenic phenotypes in patient neurons. These included nitrosative stress, accumulation of endoplasmic reticulum (ER)-associated degradation substrates, and ER stress. A small molecule identified in a yeast screen (NAB2), and the ubiquitin ligase Nedd4 it affects, reversed pathologic phenotypes in these neurons.
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
authors.forename: Chee Yeun
authors.initials: CY
authors.lastname: Chung
authors.forename: Vikram
authors.initials: V
authors.lastname: Khurana
authors.forename: Pavan K
authors.initials: PK
authors.lastname: Auluck
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Tardiff
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Mazzulli
authors.forename: Frank
authors.initials: F
authors.lastname: Soldner
authors.forename: Valeriya
authors.initials: V
authors.lastname: Baru
authors.forename: Yali
authors.initials: Y
authors.lastname: Lou
authors.forename: Yelena
authors.initials: Y
authors.lastname: Freyzon
authors.forename: Sukhee
authors.initials: S
authors.lastname: Cho
authors.forename: Alison E
authors.initials: AE
authors.lastname: Mungenast
authors.forename: Julien
authors.initials: J
authors.lastname: Muffat
authors.forename: Maisam
authors.initials: M
authors.lastname: Mitalipova
authors.forename: Michael D
authors.initials: MD
authors.lastname: Pluth
authors.forename: Nathan T
authors.initials: NT
authors.lastname: Jui
authors.forename: Birgitt
authors.initials: B
authors.lastname: Schüle
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Lippard
authors.forename: Li-Huei
authors.initials: LH
authors.lastname: Tsai
authors.forename: Dimitri
authors.initials: D
authors.lastname: Krainc
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Buchwald
authors.forename: Rudolf
authors.initials: R
authors.lastname: Jaenisch
authors.forename: Susan
authors.initials: S
authors.lastname: Lindquist
mesh_terms: D000818:Animals; D001562:Benzimidazoles / Q000737:chemistry / Q000494:pharmacology*; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D005260:Female; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism; D009154:Mutation; D055495:Neurogenesis; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism*
chemical_list: D001562:Benzimidazoles; D051844:alpha-Synuclein