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Human pyruvate dehydrogenase complex (PDC) deficiency caused by mutations of the pyruvate dehydrogenase component (PDH) of the pyruvate dehydrogenase complex (PDC) is associated with the loss of myelin in the cortex and subcortical brain regions. Similar changes occur in the heterozygous PDH+/mouse model of a partial PDC deficiency. In order to investigate the underlying mechanisms, quantitative stereological analysis of O4 expressing oligodendrocytes (OLG), double stained Ki67+/O4+ immature proliferating OLG Progenitor Cells (OPCs) and overall numbers of the proliferating cells (Ki67+) were analyzed in the brains of 35-day-old PDH+/and control PDH+/+ mice. ANOVA showed an overall depletion of all cell populations in analyzed brain regions in PDH+/mice. As a potential treatment for PDC insufficiency we tested phenylbutyrate (PB), an inhibitor of PDH kinases, to increase the residual PDC activity. In PDH+/+ mice, daily (from postnatal day 2-35) single injections of PB produced no effect, though in the PDH+/mice, PB had an overall increasing effect on O4 OLG with significant increases recorded for SVZ and SGZ. PB increased and restored depleted OPCs in PDH+/mice to the levels found in PDH+/+. In summary, loss of O4 OLG in developing PDC-deficient mice and their PB-induced recovery appear to reflect changes in their proliferating progenitors and may be beneficial for the treatment of PDC deficiency in children affected with mutations in the α subunit of PDH.

Loss of Oligodendrocytes in Mouse Model of Pyruvate Dehydrogenase Complex Deficiency and Partial Reversal by Phenylbutyrate Treatment