Oligodendrocytes depend on MCL-1 to prevent spontaneous apoptosis and white matter degeneration
Oligodendrocytes depend on MCL-1 to prevent spontaneous apoptosis and white matter degeneration
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.
Cleveland Abigail H.、Gama Vivian、Nikolova Viktoriya D.、Moy Sheryl、Gershon Timothy R.、Romero-Morales Alejandra、Herrero Melisa、Elroy-Stein Orna、Azcona Laurent Alfonso
UNC Cancer Cell Biology Training Program, University of North Carolina||Department of Neurology, UNC School of Medicine, University of North CarolinaVanderbilt University, Cell and Developmental Biology||Vanderbilt University, Vanderbilt Center for Stem Cell Biology||Vanderbilt University, Vanderbilt Brain InstituteUNC Carolina Institute for Developmental Disabilities||Department of Psychiatry, UNC School of Medicine, University of North CarolinaUNC Carolina Institute for Developmental Disabilities||Department of Psychiatry, UNC School of Medicine, University of North CarolinaDepartment of Neurology, UNC School of Medicine, University of North Carolina||UNC Neuroscience Center, University of North Carolina||Lineberger Comprehensive Cancer Center, University of North CarolinaVanderbilt University, Cell and Developmental BiologyShmunis School of Biomedicine and Cancer Research, Faculty of Life Sciences, Tel Aviv UniversityShmunis School of Biomedicine and Cancer Research, Faculty of Life Sciences, Tel Aviv University||Sagol School of Neuroscience, Tel Aviv UniversityDepartment of Neurology, UNC School of Medicine, University of North Carolina
神经病学、精神病学基础医学分子生物学
Cleveland Abigail H.,Gama Vivian,Nikolova Viktoriya D.,Moy Sheryl,Gershon Timothy R.,Romero-Morales Alejandra,Herrero Melisa,Elroy-Stein Orna,Azcona Laurent Alfonso.Oligodendrocytes depend on MCL-1 to prevent spontaneous apoptosis and white matter degeneration[EB/OL].(2025-03-28)[2025-05-28].https://www.biorxiv.org/content/10.1101/2020.12.02.408138.点此复制
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