Suppression of proteolipid protein rescues Pelizaeus-Merzbacher disease

@article{Elitt2020SuppressionOP,
  title={Suppression of proteolipid protein rescues Pelizaeus-Merzbacher disease},
  author={Matthew S Elitt and Lilianne Barbar and H. Elizabeth Shick and Berit Powers and Yuka Maeno-Hikichi and Mayur Madhavan and Kevin C. Allan and Baraa S. Nawash and Artur S Gevorgyan and Stevephen Hung and Zachary S Nevin and Hannah E. Olsen and Midori Hitomi and Daniela Schlatzer and Hien Tran Zhao and Adam Swayze and David F Lepage and Weihong Jiang and Ronald A. Conlon and Frank Rigo and Paul J. Tesar},
  journal={Nature},
  year={2020},
  volume={585},
  pages={397 - 403}
}
Mutations in PLP1 , the gene that encodes proteolipid protein (PLP), result in failure of myelination and neurological dysfunction in the X-chromosome-linked leukodystrophy Pelizaeus–Merzbacher disease (PMD) 1 , 2 . Most PLP1 mutations, including point mutations and supernumerary copy variants, lead to severe and fatal disease. Patients who lack PLP1 expression, and Plp1 -null mice, can display comparatively mild phenotypes, suggesting that PLP1 suppression might provide a general therapeutic… 
A novel non-human primate model of Pelizaeus-Merzbacher disease
Mutation of Proteolipid Protein 1 Gene: From Severe Hypomyelinating Leukodystrophy to Inherited Spastic Paraplegia
TLDR
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TLDR
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TLDR
ATAC-seq and ChIP-seq data show that Plp1-E1 and Plp2-E2 are OL-specific enhancers that are conserved among human, mouse and rat and Myrf, a master regulator of OL development, acts on Plp 1-E 1 and PlP1- E2 to promote Plp3 expression.
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TLDR
Improved understanding of hypomyelinating disorders will guide future treatment strategies, which should not only address myelin deficits but also preserve axonal health.
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TLDR
The approaches of using stem cell transplantation, gene replacement therapy, and gene editing as potential treatment options are explored, and their possible benefits and limitations are discussed as future therapeutic directions.
Emerging Concepts in Vector Development for Glial Gene Therapy: Implications for Leukodystrophies
TLDR
This work links recent advances in vectorology to glial targeting directed towards gene therapies for specific leukodystrophies and related developmental or neurometabolic disorders affecting the CNS white matter and frame strategies for therapy development in future.
Oligodendrocytes depend on MCL-1 to prevent spontaneous apoptosis and white matter degeneration
TLDR
The 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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References

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TLDR
It is shown that cholesterol itself promotes normal PLP trafficking and that dietary cholesterol influences PMD pathology, and that cholesterol treatment prevented disease progression even after onset of clinical symptoms.
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TLDR
Evidence is provided that AAV-mediated gene suppression therapy can serve as a potential cure for PMD resulting from PLP1 duplication and possibly for other genomic disorders.
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TLDR
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TLDR
PMD and similar hypomyelinating disorders are attractive therapeutic targets for neural stem cell and glial progenitor cell transplantation, efforts at which are now underway in a number of research centers.
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TLDR
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TLDR
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