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Abstract
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.
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1 University of North Carolina, UNC Cancer Cell Biology Training Program, Chapel Hill, USA (GRID:grid.410711.2) (ISNI:0000 0001 1034 1720); University of North Carolina, Department of Neurology, UNC School of Medicine, Chapel Hill, USA (GRID:grid.410711.2) (ISNI:0000 0001 1034 1720)
2 Vanderbilt University, Cell and Developmental Biology, Nashville, USA (GRID:grid.152326.1) (ISNI:0000 0001 2264 7217)
3 University of North Carolina, Department of Neurology, UNC School of Medicine, Chapel Hill, USA (GRID:grid.410711.2) (ISNI:0000 0001 1034 1720)
4 Tel Aviv University, Shmunis School of Biomedicine and Cancer Research, Faculty of Life Sciences, Tel Aviv, Israel (GRID:grid.12136.37) (ISNI:0000 0004 1937 0546)
5 UNC Carolina Institute for Developmental Disabilities, Chapel Hill, USA (GRID:grid.10698.36) (ISNI:0000000122483208); University of North Carolina, Department of Psychiatry, UNC School of Medicine, Chapel Hill, USA (GRID:grid.410711.2) (ISNI:0000 0001 1034 1720)
6 Tel Aviv University, Shmunis School of Biomedicine and Cancer Research, Faculty of Life Sciences, Tel Aviv, Israel (GRID:grid.12136.37) (ISNI:0000 0004 1937 0546); Tel Aviv University, Sagol School of Neuroscience, Tel Aviv, Israel (GRID:grid.12136.37) (ISNI:0000 0004 1937 0546)
7 Vanderbilt University, Cell and Developmental Biology, Nashville, USA (GRID:grid.152326.1) (ISNI:0000 0001 2264 7217); Vanderbilt University, Vanderbilt Center for Stem Cell Biology, Nashville, USA (GRID:grid.152326.1) (ISNI:0000 0001 2264 7217); Vanderbilt Brain Institute, Vanderbilt University, Nashville, USA (GRID:grid.152326.1) (ISNI:0000 0001 2264 7217)
8 University of North Carolina, Department of Neurology, UNC School of Medicine, Chapel Hill, USA (GRID:grid.410711.2) (ISNI:0000 0001 1034 1720); University of North Carolina, UNC Neuroscience Center, Chapel Hill, USA (GRID:grid.410711.2) (ISNI:0000 0001 1034 1720); University of North Carolina, Lineberger Comprehensive Cancer Center, Chapel Hill, USA (GRID:grid.410711.2) (ISNI:0000 0001 1034 1720)