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SURF1 mutations causative of Leigh syndrome impair human neurogenesis

Item Type:Preprint
Title:SURF1 mutations causative of Leigh syndrome impair human neurogenesis
Creators Name:Inak, G. and Rybak-Wolf, A. and Lisowski, P. and Juettner, R. and Zink, A. and Mlody, B. and Glazar, P. and Secker, C. and Ciptasari, U.H. and Stenzel, W. and Hahn, T. and Diecke, S. and Priller, J. and Gotthardt, M. and Kuehn, R. and Wanker, E.E. and Rajewsky, N. and Schuelke, M. and Prigione, A.
Abstract:Mutations in the mitochondrial complex IV assembly factor SURF1 represent a major cause of Leigh syndrome (LS), a rare fatal neurological disorder. SURF1-deficient animals have failed to recapitulate the neuronal pathology of LS, hindering our understanding of the disease mechanisms. We generated induced pluripotent stem cells from LS patients carrying homozygous SURF1 mutations (SURF1 iPS) and performed biallelic correction via CRISPR/Cas9. In contrast to corrected cells, SURF1 iPS showed impaired neuronal differentiation. Aberrant bioenergetics in SURF1 iPS occurred already in neural progenitor cells (NPCs), disrupting their neurogenic potency. Cerebral organoids from SURF1 iPS were smaller and recapitulated the neurogenesis defects. Our data imply that SURF1 mutations cause a failure in the development of maturing neurons. Using NPC function as an interventional target, we identified SURF1 gene augmentation as a potential strategy for restoring neurogenesis in LS patients carrying SURF1 mutations.
Keywords:Leigh Syndrome, SURF1, iPSCs, Neurogenesis, Brain Organoids, Mitochondria
Source:bioRxiv
Publisher:Cold Spring Harbor Laboratory Press (U.S.A.)
Article Number:551390
Date:20 February 2019
Official Publication:https://doi.org/10.1101/551390

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