title: Mitochondrial alterations by PARKIN in dopaminergic neurons using PARK2 patient-specific and PARK2 knockout isogenic iPSC lines.
abstract: In this study, we used patient-specific and isogenic PARK2-induced pluripotent stem cells (iPSCs) to show that mutations in PARK2 alter neuronal proliferation. The percentage of TH(+) neurons was decreased in Parkinson's disease (PD) patient-derived neurons carrying various mutations in PARK2 compared with an age-matched control subject. This reduction was accompanied by alterations in mitochondrial:cell volume fraction (mitochondrial volume fraction). The same phenotype was confirmed in isogenic PARK2 null lines. The mitochondrial phenotype was also seen in non-midbrain neurons differentiated from the PARK2 null line, as was the functional phenotype of reduced proliferation in culture. Whole genome expression profiling at various stages of differentiation confirmed the mitochondrial phenotype and identified pathways altered by PARK2 dysfunction that include PD-related genes. Our results are consistent with current model of PARK2 function where damaged mitochondria are targeted for degradation via a PARK2/PINK1-mediated mechanism.
authors.affiliation: Buck Institute, Novato, CA 94945, USA.
authors.forename: Atossa
authors.initials: A
authors.lastname: Shaltouki
authors.affiliation: Buck Institute, Novato, CA 94945, USA.
authors.forename: Renuka
authors.initials: R
authors.lastname: Sivapatham
authors.affiliation: Buck Institute, Novato, CA 94945, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Pei
authors.affiliation: Buck Institute, Novato, CA 94945, USA.
authors.forename: Akos A
authors.initials: AA
authors.lastname: Gerencser
authors.affiliation: Buck Institute, Novato, CA 94945, USA.
authors.forename: Olga
authors.initials: O
authors.lastname: Momčilović
authors.affiliation: NxCell Science, Novato, CA 94947, USA.
authors.forename: Mahendra S
authors.initials: MS
authors.lastname: Rao
authors.affiliation: Buck Institute, Novato, CA 94945, USA; XCell Science, Novato, CA 94947, USA. Electronic address: xzeng@buckinstitute.org.
authors.forename: Xianmin
authors.initials: X
authors.lastname: Zeng
mesh_terms: D000818:Animals; D001483:Base Sequence; D002454:Cell Differentiation; D002478:Cells, Cultured; D004272:DNA, Mitochondrial / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D057026:Induced Pluripotent Stem Cells / Q000166:cytology* / Q000378:metabolism; D007621:Karyotyping; D008928:Mitochondria / Q000378:metabolism* / Q000648:ultrastructure; D009154:Mutation; D010300:Parkinson Disease / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D060888:Real-Time Polymerase Chain Reaction; D044767:Ubiquitin-Protein Ligases / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism
chemical_list: D004272:DNA, Mitochondrial; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein
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