title: Degeneration and impaired regeneration of gray matter oligodendrocytes in amyotrophic lateral sclerosis.
abstract: Oligodendrocytes associate with axons to establish myelin and provide metabolic support to neurons. In the spinal cord of amyotrophic lateral sclerosis (ALS) mice, oligodendrocytes downregulate transporters that transfer glycolytic substrates to neurons and oligodendrocyte progenitors (NG2(+) cells) exhibit enhanced proliferation and differentiation, although the cause of these changes in oligodendroglia is unknown. We found extensive degeneration of gray matter oligodendrocytes in the spinal cord of SOD1 (G93A) ALS mice prior to disease onset. Although new oligodendrocytes were formed, they failed to mature, resulting in progressive demyelination. Oligodendrocyte dysfunction was also prevalent in human ALS, as gray matter demyelination and reactive changes in NG2(+) cells were observed in motor cortex and spinal cord of ALS patients. Selective removal of mutant SOD1 from oligodendroglia substantially delayed disease onset and prolonged survival in ALS mice, suggesting that ALS-linked genes enhance the vulnerability of motor neurons and accelerate disease by directly impairing the function of oligodendrocytes.
authors.affiliation: The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Shin H
authors.initials: SH
authors.lastname: Kang
authors.forename: Ying
authors.initials: Y
authors.lastname: Li
authors.forename: Masahiro
authors.initials: M
authors.lastname: Fukaya
authors.forename: Ileana
authors.initials: I
authors.lastname: Lorenzini
authors.forename: Don W
authors.initials: DW
authors.lastname: Cleveland
authors.forename: Lyle W
authors.initials: LW
authors.lastname: Ostrow
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Rothstein
authors.forename: Dwight E
authors.initials: DE
authors.lastname: Bergles
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000150:complications* / Q000473:pathology*; D000818:Animals; D000831:Animals, Newborn; D049109:Cell Proliferation; D002478:Cells, Cultured; D004195:Disease Models, Animal; D007839:Functional Laterality / Q000235:genetics; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009044:Motor Cortex / Q000473:pathology; D009186:Myelin Sheath / Q000378:metabolism / Q000473:pathology; D009410:Nerve Degeneration / Q000139:chemically induced / Q000209:etiology* / Q000473:pathology; D009413:Nerve Fibers, Myelinated / Q000473:pathology / Q000648:ultrastructure; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009836:Oligodendroglia / Q000187:drug effects / Q000473:pathology* / Q000648:ultrastructure; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics; D012038:Regeneration / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D013116:Spinal Cord / Q000166:cytology / Q000473:pathology; D016019:Survival Analysis
chemical_list: D009419:Nerve Tissue Proteins; D020796:Receptor, Platelet-Derived Growth Factor alpha
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