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

  • Stem Cell Reports. 2016 Oct 11;7(4):664-677. doi: 10.1016/j.stemcr.2016.08.012.
Sun Young Chung  1 ,  Sarah Kishinevsky  1 ,  Joseph R Mazzulli  2 ,  John Graziotto  2 ,  Ana Mrejeru  3 ,  Eugene V Mosharov  3 ,  Lesly Puspita  4 ,  Parvin Valiulahi  4 ,  David Sulzer  5 ,  Teresa A Milner  6 ,  Tony Taldone  7 ,  Dimitri Krainc  2 ,  Lorenz Studer  8 ,  Jae-Won Shim  9
Affiliations
  • 1. Center for Stem Cell Biology, Sloan-Kettering Institute, New York, NY 10065, USA; Developmental Biology Program, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, Box 256, New York, NY 10065, USA.
  • 2. Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
  • 3. Department of Neurology, Columbia University Medical Center, New York, NY 10032, USA.
  • 4. Soonchunhyang Institute of Medi-bio Science (SIMS), Soonchunhyang University, 25, Bongjeong-ro, Dongnam-gu, Cheonan-si 31151, Korea.
  • 5. Department of Neurology, Columbia University Medical Center, New York, NY 10032, USA; Department of Psychiatry, Columbia University Medical Center, New York, NY 10032, USA; Department of Pharmacology, Columbia University Medical Center, New York, NY 10032, USA.
  • 6. Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY 10065, USA; Harold and Margaret Milliken Hatch Laboratory of Neuroendocrinology, The Rockefeller University, New York, NY 10065, USA.
  • 7. Molecular Pharmacology and Chemistry Program, Sloan-Kettering Institute, New York, NY 10065, USA.
  • 8. Center for Stem Cell Biology, Sloan-Kettering Institute, New York, NY 10065, USA; Developmental Biology Program, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, Box 256, New York, NY 10065, USA. Electronic address: [email protected].
  • 9. Soonchunhyang Institute of Medi-bio Science (SIMS), Soonchunhyang University, 25, Bongjeong-ro, Dongnam-gu, Cheonan-si 31151, Korea. Electronic address: [email protected].
PMID: 27641647 DOI: 10.1016/j.stemcr.2016.08.012
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.