Diverse 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.
bioRxiv Subject Collection: Neuroscience