title: Parkinson's disease induced pluripotent stem cells with triplication of the α-synuclein locus.
abstract: A major barrier to research on Parkinson's disease is inaccessibility of diseased tissue for study. One solution is to derive induced pluripotent stem cells from patients and differentiate them into neurons affected by disease. Triplication of SNCA, encoding α-synuclein, causes a fully penetrant, aggressive form of Parkinson's disease with dementia. α-Synuclein dysfunction is the critical pathogenic event in Parkinson's disease, multiple system atrophy and dementia with Lewy bodies. Here we produce multiple induced pluripotent stem cell lines from an SNCA triplication patient and an unaffected first-degree relative. When these cells are differentiated into midbrain dopaminergic neurons, those from the patient produce double the amount of α-synuclein protein as neurons from the unaffected relative, precisely recapitulating the cause of Parkinson's disease in these individuals. This model represents a new experimental system to identify compounds that reduce levels of α-synuclein, and to investigate the mechanistic basis of neurodegeneration caused by α-synuclein dysfunction.
authors.affiliation: MRC Centre for Regenerative Medicine, Institute for Stem Cell Research, University of Edinburgh, Edinburgh EH9 3JQ, UK. m.devine@ion.ucl.ac.uk
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Devine
authors.forename: Mina
authors.initials: M
authors.lastname: Ryten
authors.forename: Petr
authors.initials: P
authors.lastname: Vodicka
authors.forename: Alison J
authors.initials: AJ
authors.lastname: Thomson
authors.forename: Tom
authors.initials: T
authors.lastname: Burdon
authors.forename: Henry
authors.initials: H
authors.lastname: Houlden
authors.forename: Fatima
authors.initials: F
authors.lastname: Cavaleri
authors.forename: Masumi
authors.initials: M
authors.lastname: Nagano
authors.forename: Nicola J
authors.initials: NJ
authors.lastname: Drummond
authors.forename: Jan-Willem
authors.initials: JW
authors.lastname: Taanman
authors.forename: Anthony H
authors.initials: AH
authors.lastname: Schapira
authors.forename: Katrina
authors.initials: K
authors.lastname: Gwinn
authors.forename: John
authors.initials: J
authors.lastname: Hardy
authors.forename: Patrick A
authors.initials: PA
authors.lastname: Lewis
authors.forename: Tilo
authors.initials: T
authors.lastname: Kunath
mesh_terms: D002454:Cell Differentiation; D002478:Cells, Cultured; D018628:Gene Dosage; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D010300:Parkinson Disease / Q000235:genetics* / Q000378:metabolism; D051844:alpha-Synuclein / Q000235:genetics* / Q000378:metabolism*
chemical_list: D051844:alpha-Synuclein