Oligodendrocytes depend on MCL-1 to prevent spontaneous apoptosis and white matter degeneration
| Autor: | Viktoriya D. Nikolova, Sheryl S. Moy, Vivian Gama, Orna Elroy-Stein, Melisa Herrero, Abigail H. Cleveland, Alejandra I. Romero-Morales, Timothy R. Gershon, Laurent Alfonso Azcona |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
Cancer Research
Immunology Cell death in the nervous system Apoptosis Biology Spontaneous apoptosis Article White matter Cellular and Molecular Neuroscience Mice hemic and lymphatic diseases medicine Animals Neurodegeneration Progenitor cell bcl-2-Associated X Protein QH573-671 Leukodystrophy Cell Biology medicine.disease White Matter Oligodendrocyte Phenotype Cell biology Oligodendroglia bcl-2 Homologous Antagonist-Killer Protein medicine.anatomical_structure Proto-Oncogene Proteins c-bcl-2 Myeloid Cell Leukemia Sequence 1 Protein Cerebellar hypoplasia (non-human) Cytology Demyelinating Diseases |
| Zdroj: | Cell Death & Disease Cell Death and Disease, Vol 12, Iss 12, Pp 1-12 (2021) |
| DOI: | 10.1101/2020.12.02.408138 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|