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Front Cell Neurosci. 2019 Jul 5;13:297. doi: 10.3389/fncel.2019.00297. eCollection 2019.

PARK2 Mutation Causes Metabolic Disturbances and Impaired Survival of Human iPSC-Derived Neurons.

Author information

1
Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark.
2
Oxford Parkinson's Disease Centre, Medical Sciences Division, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom.
3
Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark.
4
Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
5
Department of Experimental Medical Science, Wallenberg Neuroscience Center, Lund University, Lund, Sweden.
6
Brain Research - Inter-Disciplinary Guided Excellence, University of Southern Denmark, Odense, Denmark.

Abstract

The protein parkin, encoded by the PARK2 gene, is vital for mitochondrial homeostasis, and although it has been implicated in Parkinson's disease (PD), the disease mechanisms remain unclear. We have applied mass spectrometry-based proteomics to investigate the effects of parkin dysfunction on the mitochondrial proteome in human isogenic induced pluripotent stem cell-derived neurons with and without PARK2 knockout (KO). The proteomic analysis quantified nearly 60% of all mitochondrial proteins, 119 of which were dysregulated in neurons with PARK2 KO. The protein changes indicated disturbances in oxidative stress defense, mitochondrial respiration and morphology, cell cycle control, and cell viability. Structural and functional analyses revealed an increase in mitochondrial area and the presence of elongated mitochondria as well as impaired glycolysis and lactate-supported respiration, leading to an impaired cell survival in PARK2 KO neurons. This adds valuable insight into the effect of parkin dysfunction in human neurons and provides knowledge of disease-related pathways that can potentially be targeted for therapeutic intervention.

KEYWORDS:

Parkinson’s; metabolism; mitochondria; oxidative stress; proteomics; survival

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