Proteomics

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


ABSTRACT: 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.

INSTRUMENT(S): Q Exactive Plus

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture, Neuronal Stem Cell

DISEASE(S): Leigh Disease

SUBMITTER: Barbara Mlody  

LAB HEAD: Alessandro Prigione

PROVIDER: PXD004977 | Pride | 2017-01-31

REPOSITORIES: Pride

Dataset's files

Source:
Action DRS
AP_NIH1_1D.raw Raw
AP_NIH1_SCX_2.raw Raw
AP_NIH1_SCX_3.raw Raw
AP_NIH1_SCX_4.raw Raw
AP_NIH1_SCX_5.raw Raw
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Publications


Mitochondrial DNA (mtDNA) mutations frequently cause neurological diseases. Modeling of these defects has been difficult because of the challenges associated with engineering mtDNA. We show here that neural progenitor cells (NPCs) derived from human induced pluripotent stem cells (iPSCs) retain the parental mtDNA profile and exhibit a metabolic switch toward oxidative phosphorylation. NPCs derived in this way from patients carrying a deleterious homoplasmic mutation in the mitochondrial gene MT-  ...[more]

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