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Title:
Degeneration and impaired regeneration of gray matter oligodendrocytes in amyotrophic lateral sclerosis | Nature Neuroscience
Description:
Oligodendrocytes form myelin sheaths and provide metabolic support to axons. Using in vivo genetic fate tracing in a mouse model of amyotrophic lateral sclerosis (ALS), this study shows that there is extensive degeneration of oligodendrocytes near motor neurons prior to behavioral manifestation of disease. Although oligodendrocytes were regenerated from resident progenitors, they failed to mature and restore myelin, a feature also observed in brain and spinal cord tissue from ALS patients. Selective deletion of ALS-linked mutant SOD1 from the oligodendrocyte lineage greatly delayed disease onset, suggesting that this mutant protein impairs their ability to support motor neurons. 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.
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description:Oligodendrocytes form myelin sheaths and provide metabolic support to axons. Using in vivo genetic fate tracing in a mouse model of amyotrophic lateral sclerosis (ALS), this study shows that there is extensive degeneration of oligodendrocytes near motor neurons prior to behavioral manifestation of disease. Although oligodendrocytes were regenerated from resident progenitors, they failed to mature and restore myelin, a feature also observed in brain and spinal cord tissue from ALS patients. Selective deletion of ALS-linked mutant SOD1 from the oligodendrocyte lineage greatly delayed disease onset, suggesting that this mutant protein impairs their ability to support motor neurons. 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.
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