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Stem cell modeling of mitochondrial parkinsonism reveals key functions of OPA1

Lookup NU author(s): Dr Marzena Kurzawa-Akanbi, Professor Patrick Chinnery



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


OBJECTIVE: Defective mitochondrial function attributed to optic atrophy 1 (OPA1) mutations causes primarily optic atrophy and, less commonly, neurodegenerative syndromes. The pathomechanism by which OPA1 mutations trigger diffuse loss of neurons in some, but not all, patients is unknown. Here, we used a tractable induced pluripotent stem cell (iPSC)-based model to capture the biology of OPA1 haploinsufficiency in cases presenting with classic eye disease versus syndromic parkinsonism.METHODS: iPSCs were generated from 2 patients with OPA1 haploinsufficiency and 2 controls and differentiated into dopaminergic neurons. Metabolic profile was determined by extracellular flux analysis, respiratory complex levels using immunoblotting, and complex I activity by a colorimetric assay. Mitochondria were examined by transmission electron microscopy. Mitochondrial DNA copy number and deletions were assayed using long-range PCR. Mitochondrial membrane potential was measured by tetramethylrhodamine methyl ester uptake, and mitochondrial fragmentation was assessed by confocal microscopy. Exome sequencing was used to screen for pathogenic variants.RESULTS: OPA1 haploinsufficient iPSCs differentiated into dopaminergic neurons and exhibited marked reduction in OPA1 protein levels. Loss of OPA1 caused a late defect in oxidative phosphorylation, reduced complex I levels, and activity without a significant change in the ultrastructure of mitochondria. Loss of neurons in culture recapitulated dopaminergic degeneration in syndromic disease and correlated with mitochondrial fragmentation.INTERPRETATION: OPA1 levels maintain oxidative phosphorylation in iPSC-derived neurons, at least in part, by regulating the stability of complex I. Severity of OPA1 disease associates primarily with the extent of OPA1-mediated fusion, suggesting that activation of this mechanism or identification of its genetic modifiers may have therapeutic or prognostic value.

Publication metadata

Author(s): Jonikas M, Madill M, Mathy A, Zekoll T, Zois CE, Wigfield S, Kurzawa-Akanbi M, Browne C, Sims D, Chinnery PF, Cowley SA, Tofaris GK

Publication type: Article

Publication status: Published

Journal: Annals of Neurology

Year: 2018

Volume: 83

Issue: 5

Pages: 915-925

Print publication date: 01/05/2018

Online publication date: 31/03/2018

Acceptance date: 23/03/2018

Date deposited: 18/06/2018

ISSN (print): 0364-5134

ISSN (electronic): 1531-8249

Publisher: John Wiley & Sons, Inc.


DOI: 10.1002/ana.25221

PubMed id: 29604226


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