MassIVE MSV000080849

Imported Reanalysis Dataset Public PXD004977

Enabling phenotypic drug discovery for neurological mitochondrial DNA disorders with patient-derived neural progenitor cells

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Description

Mitochondrial DNA (mtDNA) mutations predominantly cause neurological diseases. Searching for therapeutic strategies is hindered by the absence of viable neural model systems due to the challenges of engineering mtDNA. We demonstrate that neural progenitor cells (NPCs), rapidly obtained from human induced pluripotent stem cells (iPSCs), retain the parental mtDNA profile and exhibit mitochondrial maturation coupled with a metabolic switch away from glycolysis. Altered calcium homeostasis and mitochondrial hyperpolarization, both potential causes of neural impairment, were observed in iPSC-derived NPCs from patients carrying a deleterious homoplasmic mutation in the mitochondrial gene MT-ATP6 (m.9185T>C). Phenotype-based high-content screenings (HCS) with FDA-approved compounds were carried out, leading to the identification of possible innovative counteracting agents. We propose iPSC-derived NPCs, displaying mild proliferative properties and proper genotype/metabotype, as a bona fide model system for the establishment of personalized phenotypic drug discovery for untreatable mtDNA disorders affecting the nervous system. Associated GEO accession number: GSE70071. [dataset license: CC0 1.0 Universal (CC0 1.0)]

Keywords: neural progenitors ; NPCs ; iPSCs ; mitochondrial disorders ; mtDNA mutations ; MT-ATP6

Contact

Principal Investigators:
(in alphabetical order) 		Alessandro Prigione, Max Delbrueck Center for Molecular Medicine (MDC), Berlin, Germany, N/A
Submitting User: ccms

Publications

Lorenz C, Lesimple P, Bukowiecki R, Zink A, Inak G, Mlody B, Singh M, Semtner M, Mah N, Auré K, Leong M, Zabiegalov O, Lyras EM, Pfiffer V, Fauler B, Eichhorst J, Wiesner B, Huebner N, Priller J, Mielke T, Meierhofer D, Izsvák Z, Meier JC, Bouillaud F, Adjaye J, Schuelke M, Wanker EE, Lombès A, Prigione A.
Human iPSC-Derived Neural Progenitors Are an Effective Drug Discovery Model for Neurological mtDNA Disorders.
Cell Stem Cell. Epub 2017 Jan 25.

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Originally identified proteins that were automatically remapped by MassIVE to proteins in the SwissProt human reference database.

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Number of distinct proteins found to be differentially abundant in at least one comparison across all analyses (original submission and reanalyses) associated with this dataset.

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Distinct protein accessions are counted across all files submitted in the "Statistical Analysis of Quantified Analytes" category having a "Protein" column in this dataset.

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