Investigation of the energy expenditure of human iPS cell-derived basal ganglia neurons from patients with Leigh syndrome
Final Report Abstract
In our project, we have demonstrated that the technology of iPSC reprogramming can be used to investigate rare neurological diseases such as Leigh syndrome (LS) that are currently incurable. We have generated innovative patient-derived neural model systems and used them to gain new knowledge regarding the mechanisms underlying the neuronal pathology associated with LS. We identified targets of intervention and discovered that PDE5 inhibitors may be considered for the treatment of LS caused by MT-ATP6 mutations. We were positively surprised that neural progenitor cells (NPCs) do predominantly rely on mitochondrial metabolism and thus exhibit aberrant functionality in the context of the mitochondrial disease LS. On the mechanistic side, these findings implicate a neurogenesis defect as the basic pathogenetic mechanism of LS. On the translational side, the data support the use of NPCs as an effective model system for LS to conduct high-throughput drug discovery and drug repurposing studies. We believe that our findings are important for not only to the scientific community in the field of stem cells and mitochondria, but may also be worth sharing with the patient community and the general public. LS and mitochondrial diseases are rare orphan disorders that suffer from a lack of therapeutic options and often from a lack of interest from the general public. Affected patients and related families may be interested to hear about our scientific advances that may soon bring potential treatment options to some of the affected individuals.
Publications
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A Glycolytic Solution for Pluripotent Stem Cells. Cell Stem Cell. 2016, Oct 6;19(4):419-420
Mlody B, Prigione A
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A movement disorder with dystonia and ataxia caused by a mutation in the HIBCH gene. Mov Dis. 2016, Nov;31(11):1733-39
Schottmann G, Sarpong A, Lorenz C, Weinhold N, Gill E, Teschner L, Wanders RJA, Prigione A, Schuelke M
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Energy metabolism in neuronal/glial induction and in iPSC models of brain disorders. Semin Cell Dev Biol. 2016 Apr;52:102-9
Mlody B, Lorenz C, Inak G, Prigione A
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Human iPSC-derived neural progenitors are an effective drug discovery model for neurological mtDNA disorders. Cell Stem Cell. 2017, May 4;20(5):659-674
Lorenz C, Lesimple P, Bukowiecki R, Zink A, Inak G, Mlody B, Singh M, Semtner M, Mah N, Leong M, Auré K, Pfiffer V, Fauler B, Eichhorst J, Lyras EM, Wiesner B, Priller J, Huebner N, Mielke T, Meierhofer D, Izsvák Z, Meier JC, Bouillaud F, Adjaye J, Wanker E, Schuelke M, Lombès A, Prigione A
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iPSC-based drug discovery for mitochondrial disease. Stem Cells. 2017 Jul;35(7):1655-1662
Inak G, Lorenz C, Lisowski P, Zink A, Mlody B, Prigione A
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Mitochondrial metabolism in early neural fate and its relevance in neuronal disease modeling. Curr Opin Cell Biol. 2017 Dec;49:71-76
Lorenz C, Prigione A
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Mitochondria and the dynamic control of stem cell homeostasis. EMBO Rep. 2018, May;19(5)
Lisowski P, Kannan P, Mlody B, Prigione A
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Pluripotent stem cells for uncovering the role of mitochondria in human brain function and dysfunction. J Mol Biol. 2018 Feb 16
Zink A, Priller J, Prigione A
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SURF1 mutations causative of Leigh syndrome impair human neurogenesis
Inak G, Rybak-Wolf A, Lisowski P, Jüttner R, Zink A, Mlody B, Glažar P, Secker C, Ciptasari UH, Stenzel W, Hahn T, Diecke S, Priller J, Gotthardt M, Kühn R, Wanker EE, Rajewsky N, Schuelke M, Prigione A
