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

• Published in: Stem cell reports Vol. 7; no. 4; pp. 664 - 677
• Main Authors: Chung, Sun Young, Kishinevsky, Sarah, Mazzulli, Joseph R., 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
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 11-10-2016; Elsevier
• Subjects: alpha-Synuclein - metabolism; Animals; Cell Differentiation; Cell Line; Dopamine - metabolism; Dopaminergic Neurons - cytology; Dopaminergic Neurons - metabolism; Humans; Induced Pluripotent Stem Cells - cytology; Induced Pluripotent Stem Cells - metabolism; Mesencephalon - cytology; Mesencephalon - metabolism; Mice; Mitochondria - metabolism; Mitochondria - ultrastructure; Models, Biological; Mutation; Organ Specificity; Parkinson Disease - genetics; Parkinson Disease - metabolism; Protein Kinases - genetics; Stress, Physiological; Ubiquitin-Protein Ligases - genetics
• ISSN: 2213-6711; 2213-6711
• DOI: 10.1016/j.stemcr.2016.08.012

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.
•Disease modeling study with patient (monogenic)-derived iPSC for Parkinson's disease•Disease phenotypes exhibited by PD iPSC-derived midbrain DA neurons involved•Mitochondria, α-synuclein, selective vulnerability, and neurotransmitter regulation•These phenotypes may interact synergistically throughout PD progression
Shim, Studer, and colleagues demonstrate that using a floor-plate-based differentiation strategy, Parkinson's disease (PD) patient iPSC-derived mDA neurons recapitulate several PD phenotypes, including pathogenic protein accumulation, cell-type-specific vulnerability, mitochondrial dysfunction, and abnormal neurotransmitter homeostasis. The authors further propose that these phenotypes form a pathogenic loop contributing to disease.