In order to dissect the molecular mechanisms underlying the neuronal pathology in Leigh syndrome (LS) patients carrying homozygous SURF1 mutations (LS SURF1), induced pluripotent stem cells from LS SURF1 patients (SURF1 iPS) were generated. Neuronal cultures and cerebral organoids derived from SURF1 iPS exhibited features indicative of impaired neurogenesis. Bioenergetic dysfunction occurred already at the level of neural progenitor cells (NPCs), and led to defects in neuronal generation and maturation, disrupting the branching capacity and firing activity of neurons. Biallelic correction of SURF1 mutation via CRISPR/Cas9 genome editing reverted the phenotypes. The data imply that LS SURF1 causes a failure in the development of maturing neurons. The authors employed NPC function as an interventional target and discovered that wild-type SURF1 over-expression was effective in improving NPC bioenergetics and promoting neurogenesis. Altogether, the authors propose aberrant neurogenesis as a central pathogenetic mechanism in LS SURF1 and suggest a potential strategy for restoring neuronal function in the fatal pediatric disease Leigh syndrome.
SURF1 mutations causative of Leigh syndrome impair human neurogenesis
Markus Schülke(1), Nikolaus Rajewsky(2), Alessandro Prigione(2)
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