Human iPSC-Derived Neural Progenitors Are an Effective Drug Discovery Model for Neurological mtDNA Disorders

Publication date: Available online 26 January 2017
Source:Cell Stem Cell
Author(s): Carmen Lorenz, Pierre Lesimple, Raul Bukowiecki, Annika Zink, Gizem Inak, Barbara Mlody, Manvendra Singh, Marcus Semtner, Nancy Mah, Karine Auré, Megan Leong, Oleksandr Zabiegalov, Ekaterini-Maria Lyras, Vanessa Pfiffer, Beatrix Fauler, Jenny Eichhorst, Burkhard Wiesner, Norbert Huebner, Josef Priller, Thorsten Mielke, David Meierhofer, Zsuzsanna Izsvák, Jochen C. Meier, Frédéric Bouillaud, James Adjaye, Markus Schuelke, Erich E. Wanker, Anne Lombès, Alessandro Prigione
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-ATP6 (m.9185T>C) showed defective ATP production and abnormally high mitochondrial membrane potential (MMP), plus altered calcium homeostasis, which represents a potential cause of neural impairment. High-content screening of FDA-approved drugs using the MMP phenotype highlighted avanafil, which we found was able to partially rescue the calcium defect in patient NPCs and differentiated neurons. Overall, our results show that iPSC-derived NPCs provide an effective model for drug screening to target mtDNA disorders that affect the nervous system.

Graphical abstract

Teaser

Prigione and colleagues show that neural progenitors differentiated from patient-derived iPSCs are an effective modeling tool for neuronal disease associated with mtDNA mutations and can be used for drug screening.


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