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

Sun Young Chung, Sarah Kishinevsky, Joseph R. Mazzulli, John Graziotto, Ana Mrejeru, Eugene V. Mosharov, Lesly Puspita, Parvin Valiulahi, David Sulzer, Teresa A. Milner, Tony Taldone, Dimitri Krainc, Lorenz Studer*, Jae won Shim

*Corresponding author for this work

Research output: Contribution to journalArticle

72 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)664-677
Number of pages14
JournalStem cell reports
Volume7
Issue number4
DOIs
StatePublished - Oct 11 2016

ASJC Scopus subject areas

  • Biochemistry
  • Genetics
  • Developmental Biology
  • Cell Biology

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    Chung, S. Y., Kishinevsky, S., Mazzulli, J. R., Graziotto, J., Mrejeru, A., Mosharov, E. V., Puspita, L., Valiulahi, P., Sulzer, D., Milner, T. A., Taldone, T., Krainc, D., Studer, L., & Shim, J. W. (2016). Parkin and PINK1 Patient iPSC-Derived Midbrain Dopamine Neurons Exhibit Mitochondrial Dysfunction and α-Synuclein Accumulation. Stem cell reports, 7(4), 664-677. https://doi.org/10.1016/j.stemcr.2016.08.012