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

Sun Young Chung, Sarah Kishinevsky, Joe 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

52 Citations (Scopus)

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

Fingerprint

Synucleins
Induced Pluripotent Stem Cells
Dopaminergic Neurons
Mesencephalon
Stem cells
Neurons
Parkinson Disease
Dopamine
Phenotype
Substantia Nigra
Mitochondria
Neurotransmitter Agents
Homeostasis
Technology
Mutation

ASJC Scopus subject areas

  • Biochemistry
  • Genetics
  • Developmental Biology
  • Cell Biology

Cite this

Chung, Sun Young ; Kishinevsky, Sarah ; Mazzulli, Joe ; Graziotto, John ; Mrejeru, Ana ; Mosharov, Eugene V. ; Puspita, Lesly ; Valiulahi, Parvin ; Sulzer, David ; Milner, Teresa A. ; Taldone, Tony ; Krainc, Dimitri ; Studer, Lorenz ; Shim, Jae won. / Parkin and PINK1 Patient iPSC-Derived Midbrain Dopamine Neurons Exhibit Mitochondrial Dysfunction and α-Synuclein Accumulation. In: Stem cell reports. 2016 ; Vol. 7, No. 4. pp. 664-677.
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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.",
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Chung, SY, Kishinevsky, S, Mazzulli, J, Graziotto, J, Mrejeru, A, Mosharov, EV, Puspita, L, Valiulahi, P, Sulzer, D, Milner, TA, Taldone, T, Krainc, D, Studer, L & Shim, JW 2016, 'Parkin and PINK1 Patient iPSC-Derived Midbrain Dopamine Neurons Exhibit Mitochondrial Dysfunction and α-Synuclein Accumulation', Stem cell reports, vol. 7, no. 4, pp. 664-677. https://doi.org/10.1016/j.stemcr.2016.08.012

Parkin and PINK1 Patient iPSC-Derived Midbrain Dopamine Neurons Exhibit Mitochondrial Dysfunction and α-Synuclein Accumulation. / Chung, Sun Young; Kishinevsky, Sarah; Mazzulli, Joe; Graziotto, John; Mrejeru, Ana; Mosharov, Eugene V.; Puspita, Lesly; Valiulahi, Parvin; Sulzer, David; Milner, Teresa A.; Taldone, Tony; Krainc, Dimitri; Studer, Lorenz; Shim, Jae won.

In: Stem cell reports, Vol. 7, No. 4, 11.10.2016, p. 664-677.

Research output: Contribution to journalArticle

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AU - Chung, Sun Young

AU - Kishinevsky, Sarah

AU - Mazzulli, Joe

AU - Graziotto, John

AU - Mrejeru, Ana

AU - Mosharov, Eugene V.

AU - Puspita, Lesly

AU - Valiulahi, Parvin

AU - Sulzer, David

AU - Milner, Teresa A.

AU - Taldone, Tony

AU - Krainc, Dimitri

AU - Studer, Lorenz

AU - Shim, Jae won

PY - 2016/10/11

Y1 - 2016/10/11

N2 - 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.

AB - 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.

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DO - 10.1016/j.stemcr.2016.08.012

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