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Parkin and PINK1 Patient iPSC-Derived Midbrain Dopamine Neurons Exhibit Mitochondrial Dysfunction and α-Synuclein Accumulation.

TitleParkin and PINK1 Patient iPSC-Derived Midbrain Dopamine Neurons Exhibit Mitochondrial Dysfunction and α-Synuclein Accumulation.
Publication TypeJournal Article
Year of Publication2016
AuthorsChung SYoung, Kishinevsky S, Mazzulli JR, Graziotto J, Mrejeru A, Mosharov EV, Puspita L, Valiulahi P, Sulzer D, Milner TA, Taldone T, Krainc D, Studer L, Shim J-W
JournalStem Cell Reports
Volume7
Issue4
Pagination664-677
Date Published2016 10 11
ISSN2213-6711
Keywordsalpha-Synuclein, Animals, Cell Differentiation, Cell Line, Dopamine, Dopaminergic Neurons, Humans, Induced Pluripotent Stem Cells, Mesencephalon, Mice, Mitochondria, Models, Biological, Mutation, Organ Specificity, Parkinson Disease, Protein Kinases, Stress, Physiological, Ubiquitin-Protein Ligases
Abstract

Parkinson's disease (PD) is characterized by the selective loss of dopamine neurons in the substantia nigra; however, the mechanism of neurodegeneration in PD remains unclear. A subset of familial PD is linked to mutations in PARK2 and PINK1, which lead to dysfunctional mitochondria-related proteins Parkin and PINK1, suggesting that pathways implicated in these monogenic forms could play a more general role in PD. We demonstrate that the identification of disease-related phenotypes in PD-patient-specific induced pluripotent stem cell (iPSC)-derived midbrain dopamine (mDA) neurons depends on the type of differentiation protocol utilized. In a floor-plate-based but not a neural-rosette-based directed differentiation strategy, iPSC-derived mDA neurons recapitulate PD phenotypes, including pathogenic protein accumulation, cell-type-specific vulnerability, mitochondrial dysfunction, and abnormal neurotransmitter homeostasis. We propose that these form a pathogenic loop that contributes to disease. Our study illustrates the promise of iPSC technology for examining PD pathogenesis and identifying therapeutic targets.

DOI10.1016/j.stemcr.2016.08.012
Alternate JournalStem Cell Reports
PubMed ID27641647
PubMed Central IDPMC5063469
Grant ListR01 NS092823 / NS / NINDS NIH HHS / United States
P50 NS038370 / NS / NINDS NIH HHS / United States
R01 NS052671 / NS / NINDS NIH HHS / United States
R01 DA008259 / DA / NIDA NIH HHS / United States
P30 CA008748 / CA / NCI NIH HHS / United States
R01 HL098351 / HL / NHLBI NIH HHS / United States
U24 NS078338 / NS / NINDS NIH HHS / United States