Neurologic disorders often disproportionately affect specific brain regions, and different apoptotic mechanisms may contribute to white matter pathology in leukodystrophies or gray matter pathology in poliodystrophies. We previously showed that neural progenitors that generate cerebellar gray matter depend on the anti-apoptotic protein BCL-xL. Conditional deletion of Bcl-xL in these progenitors produces spontaneous apoptosis and cerebellar hypoplasia, while similar conditional deletion of Mcl-1 produces no phenotype. Here we show that, in contrast, postnatal oligodendrocytes depend on MCL-1. We found that brain-wide Mcl-1 deletion caused apoptosis specifically in mature oligodendrocytes while sparing astrocytes and oligodendrocyte precursors, resulting in impaired myelination and progressive white matter degeneration. Disabling apoptosis through co-deletion of Bax or Bak rescued white matter degeneration, implicating the intrinsic apoptotic pathway in Mcl-1-dependence. Bax and Bak co-deletions rescued different aspects of the Mcl-1-deleted phenotype, demonstrating their discrete roles in white matter stability. MCL-1 protein abundance was reduced in eif2b5-mutant mouse model of the leukodystrophy vanishing white matter disease (VWMD), suggesting the potential for MCL-1 deficiency to contribute to clinical neurologic disease. Our data show that oligodendrocytes require MCL-1 to suppress apoptosis, implicate MCL-1 deficiency in white matter pathology, and suggest apoptosis inhibition as a leukodystrophy therapy.
SUMMARYDiverse mutations cause leukodystrophies through unresolved processes. Developing leukodystrophy therapies requires identifying mechanisms that operate downstream of causative mutations to produce white matter degeneration. We have identified the apoptosis regulator MCL-1 as required for white matter stability and depleted by leukodystrophy-causing mutations. Brain-specific deletion of Mcl-1 in mice recapitulates progressive leukodystrophy, with MRI changes, decreased oligodendrocytes, and astrocytic and microglial changes typical of Vanishing White Matter Disease (VWMD). Disabling apoptosis through co-deletion of Bax or Bak rescued white matter Mcl-1-dependence, broadly implicating the intrinsic apoptotic pathway in leukodystrophy pathogenesis. Bax and Bak co-deletions rescued different aspects of the Mcl-1-deleted phenotype, demonstrating their discrete roles in white matter stability. MCL-1 protein abundance was reduced in eif2b5-mutant mice that model VWMD, suggesting a mechanistic relationship between MCL-1 and VWMD. Our data show that oligodendrocytes require MCL-1 to suppress apoptosis, implicate MCL-1 loss in VWMD pathogenesis, and suggest inhibiting apoptosis for leukodystrophy therapy.
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