NG2 cells response to axonal alteration in the spinal cord white matter in mice with genetic disruption of neurofilament light subunit expression

Wu, Yajun; Tang, Ya Fang; Xiao, Zhi‐Cheng; Bao, Zhen Min; He, Bei

doi:10.1186/1750-1326-3-18

Cited by 13 publications

(8 citation statements)

References 35 publications

(37 reference statements)

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“…Widespread axonal degeneration can lead to loss of oligodendrocytes and reactive changes in their progenitors 21, 22 , raising the possibility that degeneration of gray matter oligodendrocytes in ALS mice is secondary to motor neuron degeneration. To address whether loss of motor neurons is sufficient to induce mobilization of NG2 + cells, we partially ablated motor neurons by injecting ricin into the sciatic nerve 23 .…”

Section: Resultsmentioning

confidence: 99%

Degeneration and impaired regeneration of gray matter oligodendrocytes in amyotrophic lateral sclerosis

et al. 2013

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Oligodendrocytes associate with axons to establish myelin and provide metabolic support to neurons. In the spinal cord of 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. Here we report that there is extensive degeneration of gray matter oligodendrocytes in the spinal cord of ALS mice before disease onset. Although new oligodendrocytes were formed, they failed to mature, resulting in progressive demyelination. Oligodendrocyte dysfunction also is 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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Section: Resultsmentioning

confidence: 99%

Degeneration and impaired regeneration of gray matter oligodendrocytes in amyotrophic lateral sclerosis

et al. 2013

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“…NG2 has been demonstrated to be oligodendrocyte precursors (Kang et al, 2010; Nishiyama et al, 2009), and they promote oligodendrocytes proliferation during brain development and even in response to injury and demyelination (Girolamo et al, 2011; Kang et al, 2010). Indeed, NG2 has been considered an early sensor to deliver information about pathological changes in neurons to the local environment (Wu et al, 2008). Therefore, ethanol‐induced upregulation of NG2 might occur to compensate the myelin dysfunctions and neural damage observed in ethanol‐treated WT mice.…”

Section: Discussionmentioning

confidence: 99%

Toll‐like receptor 4 participates in the myelin disruptions associated with chronic alcohol abuse

Alfonso-Loeches

Pascual

Gómez‐Pinedo

et al. 2012

Glia

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Alcohol abuse and alcoholism can cause brain damage, loss of white matter, myelin fiber disruption, and even neuronal injury. The underlying mechanisms of these alterations remain elusive. We have shown that chronic ethanol intake, by activating glial toll-like receptor 4 (TLR4) receptors, triggers the production of inflammatory mediators and can cause brain damage. Because neuroinflammation may be associated with demyelination and neuronal damage, we evaluate whether the ethanol-induced TLR4-dependent proinflammatory environment in the brain could be involved in the myelin disruptions observed in alcoholics. Using brains from wild-type (WT) and TLR4 knockout (KO, TLR4(-/-) ) mice, we demonstrate that chronic ethanol treatment downregulated proteins involved in myelination [proteolipid protein (PLP), myelin basic protein (MBP), myelin-oligodendrocyte glycoprotein, 2,3-cyclic-nucleotide-3-phosphodiesterase, and myelin-associated glycoprotein], while increased chondroitin sulfate proteoglycan NG2 (NG2)-proteoglycan in several brain regions of ethanol-treated WT mice. The immunohistochemistry analysis also revealed that ethanol-treatment-altered myelin morphology reduced the number of MBP-positive fibers and caused oligodendrocyte death, as demonstrated by an increase in caspase-3-positive oligodendrocytes. The in vivo imaging system further confirmed that chronic ethanol intake markedly reduced the PLP in WT mice. Most myelin alterations were not observed in brains from ethanol-treated TLR4(-/-) mice. Electron microscopy studies revealed that although 41-47% of axons showed myelin sheath disarrangements in the cerebral cortex and corpus callosum of WT ethanol-treated mice, respectively, small focal fiber disruptions were noticed in these brain areas of ethanol-treated TLR4(-/-) mice. In summary, the present results suggest that ethanol-induced neuroinflammation might be involved in myelin disruptions and white matter loss observed in human alcoholics.

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“…More recently, Monsma et al ( 2014 ) have shown that myelinating cells can regulate the rate of NF transport, resulting in local accumulation and expansion of the axonal diameter (Monsma et al, 2014 ), a process for which phosphorylation is most likely the mediator, given its upregulation during the process of myelination and studies such as Lee et al ( 2014 ), who demonstrated that MAPK cascades control anterograde transport of NFs. NF content does not determine the overall level of myelination: there are no significant differences in the expression of MAG between wildtype and NF knockouts (Wu et al, 2008 ). Although there appears to be no direct relationship between the level of myelination of an axon and its NF content, the level of myelination may nonetheless affect the level of axonal NF phosphorylation.…”

Section: Posttranslational Modifications Of Neurofilamentsmentioning

confidence: 99%

Diffuse axonal injury in brain trauma: insights from alterations in neurofilaments

Siedler

Chuah

Kirkcaldie

et al. 2014

Front. Cell. Neurosci.

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Traumatic brain injury (TBI) from penetrating or closed forces to the cranium can result in a range of forms of neural damage, which culminate in mortality or impart mild to significant neurological disability. In this regard, diffuse axonal injury (DAI) is a major neuronal pathophenotype of TBI and is associated with a complex set of cytoskeletal changes. The neurofilament triplet proteins are key structural cytoskeletal elements, which may also be important contributors to the tensile strength of axons. This has significant implications with respect to how axons may respond to TBI. It is not known, however, whether neurofilament compaction and the cytoskeletal changes that evolve following axonal injury represent a component of a protective mechanism following damage, or whether they serve to augment degeneration and progression to secondary axotomy. Here we review the structure and role of neurofilament proteins in normal neuronal function. We also discuss the processes that characterize DAI and the resultant alterations in neurofilaments, highlighting potential clues to a possible protective or degenerative influence of specific neurofilament alterations within injured neurons. The potential utility of neurofilament assays as biomarkers for axonal injury is also discussed. Insights into the complex alterations in neurofilaments will contribute to future efforts in developing therapeutic strategies to prevent, ameliorate or reverse neuronal degeneration in the central nervous system (CNS) following traumatic injury.

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NG2 cells response to axonal alteration in the spinal cord white matter in mice with genetic disruption of neurofilament light subunit expression

Cited by 13 publications

References 35 publications

Degeneration and impaired regeneration of gray matter oligodendrocytes in amyotrophic lateral sclerosis

Degeneration and impaired regeneration of gray matter oligodendrocytes in amyotrophic lateral sclerosis

Toll‐like receptor 4 participates in the myelin disruptions associated with chronic alcohol abuse

Diffuse axonal injury in brain trauma: insights from alterations in neurofilaments

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