Oligodendrocytes depend on MCL-1 to prevent spontaneous apoptosis and white matter degeneration

Abigail H. Cleveland, Alejandra Romero-Morales, Laurent Alfonso Azcona, Melisa Herrero, Viktoriya D. Nikolova, Sheryl Moy, Orna Elroy-Stein, Vivian Gama, Timothy R. Gershon*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

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.

Original languageEnglish
Article number1133
JournalCell Death and Disease
Volume12
Issue number12
DOIs
StatePublished - Dec 2021

Funding

FundersFunder number
National Cancer InstituteR21CA227483
National Institute of General Medical SciencesU54HD079124
National Institute of Neurological Disorders and StrokeR01NS106227, T32CA071341, R01NS088219, R01NS102627
Eunice Kennedy Shriver National Institute of Child Health and Human Development

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