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Leukodystrophy caused by plasmalogen deficiency rescued by glyceryl 1-myristyl ether treatment.

Authors
  • Malheiro, Ana R1, 2
  • Correia, Barbara1
  • Ferreira da Silva, Tiago1
  • Bessa-Neto, Diogo1
  • Van Veldhoven, Paul P3
  • Brites, Pedro1
  • 1 Neurolipid Biology, Instituto de Investigação e Inovação em Saúde - i3S, Instituto de Biologia Molecular e Celular - IBMC e Universidade do Porto, Porto, Portugal. , (Portugal)
  • 2 ICBAS, Instituto Ciências Biomédicas Abel Salazar, Porto, Portugal. , (Portugal)
  • 3 Laboratory of Lipid Biochemistry and Protein Interactions (LIPIT), KU Leuven, Leuven, Belgium. , (Belgium)
Type
Published Article
Journal
Brain Pathology
Publisher
Wiley (Blackwell Publishing)
Publication Date
Sep 01, 2019
Volume
29
Issue
5
Pages
622–639
Identifiers
DOI: 10.1111/bpa.12710
PMID: 30667116
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Plasmalogens are the most abundant form of ether phospholipids in myelin and their deficiency causes Rhizomelic Chondrodysplasia Punctata (RCDP), a severe developmental disorder. Using the Gnpat-knockout (KO) mouse as a model of RCDP, we determined the consequences of a plasmalogen deficiency during myelination and myelin homeostasis in the central nervous system (CNS). We unraveled that the lack of plasmalogens causes a generalized hypomyelination in several CNS regions including the optic nerve, corpus callosum and spinal cord. The defect in myelin content evolved to a progressive demyelination concomitant with generalized astrocytosis and white matter-selective microgliosis. Oligodendrocyte precursor cells (OPC) and mature oligodendrocytes were abundant in the CNS of Gnpat KO mice during the active period of demyelination. Axonal loss was minimal in plasmalogen-deficient mice, although axonal damage was observed in spinal cords from aged Gnpat KO mice. Characterization of the plasmalogen-deficient myelin identified myelin basic protein and septin 7 as early markers of dysmyelination, whereas myelin-associated glycoprotein was associated with the active demyelination phase. Using in vitro myelination assays, we unraveled that the intrinsic capacity of oligodendrocytes to ensheath and initiate membrane wrapping requires plasmalogens. The defect in plasmalogens was rescued with glyceryl 1-myristyl ether [1-O-tetradecyl glycerol (1-O-TDG)], a novel alternative precursor in the plasmalogen biosynthesis pathway. 1-O-TDG treatment rescued myelination in plasmalogen-deficient oligodendrocytes and in mutant mice. Our results demonstrate the importance of plasmalogens for oligodendrocyte function and myelin assembly, and identified a novel strategy to promote myelination in nervous tissue. © 2019 International Society of Neuropathology.

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