Myelin Basic Protein Induces Neuron-Specific Toxicity by Directly Damaging the Neuronal Plasma Membrane

Zhang, Jie; X, Sun; Zheng, Shuier; Liu, Xiao; Jin, Jinghua; Ren, Yi; Luo, Jianhong

doi:10.1371/journal.pone.0108646

Cited by 30 publications

(34 citation statements)

References 85 publications

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“…However, in chronic EAE sections MBP accumulated also around neuronal cells, such as Purkinje cells, as can be seen in sections Figure 4 E and F. Indeed, it was recently shown that MBP binding may induce neuron-specific toxicity by direct damaging the neuronal plasma membrane integrity. 41 Consistent with this, our results indicate that following demyelination, new MBP aggregates may damage neuronal cells by a prion-like mechanism. 42 …”

Section: Resultssupporting

confidence: 90%

“… 19 In the brains of mice suffering from chronic EAE, it can be the reduced levels of cholesterol and other lipids which may preclude the entrance of MBP to its appropriate location in the myelin sheath and induce its aggregation outside the membrane. Outside the membrane, aggregated MBP may damage neighboring neurons, 41 promoting further neurodegeneration. It remains to be established whether changes in lipid composition result or encourage the demyelinating process.…”

Section: Discussionmentioning

confidence: 99%

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Aggregation of MBP in chronic demyelination

Frid

Einstein

Friedman-Levi

et al. 2015

Ann Clin Transl Neurol

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ObjectivesMisfolding of key disease proteins to an insoluble state is associated with most neurodegenerative conditions, such as prion, Parkinson, and Alzheimer’s diseases. In this work, and by studying animal models of multiple sclerosis, we asked whether this is also the case for myelin basic protein (MBP) in the late and neurodegenerative phases of demyelinating diseases.MethodsTo this effect, we tested whether MBP, an essential myelin component, present prion-like properties in animal models of MS, as is the case for Cuprizone-induced chronic demyelination or chronic phases of Experimental Autoimmune Encephalomyelitis (EAE).ResultsWe show here that while total levels of MBP were not reduced following extensive demyelination, part of these molecules accumulated thereafter as aggregates inside oligodendrocytes or around neuronal cells. In chronic EAE, MBP precipitated concomitantly with Tau, a marker of diverse neurodegenerative conditions, including MS. Most important, analysis of fractions from Triton X-100 floatation gradients suggest that the lipid composition of brain membranes in chronic EAE differs significantly from that of naïve mice, an effect which may relate to oxidative insults and subsequently prevent the appropriate insertion and compaction of new MBP in the myelin sheath, thereby causing its misfolding and aggregation.InterpretationPrion-like aggregation of MBP following chronic demyelination may result from an aberrant lipid composition accompanying this pathological status. Such aggregation of MBP may contribute to neuronal damage that occurs in the progressive phase of MS.

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Section: Resultssupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Aggregation of MBP in chronic demyelination

Frid

Einstein

Friedman-Levi

et al. 2015

Ann Clin Transl Neurol

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“…MBP displays direct neuron-specific (but not glial) toxicity in vitro, which seems to depend on its binding to sialic acid-containing lipids on the neuronal surface and regulation of the nonselective cation flow [79, 80]. Both in the presence and absence of T cells, IS MBP84-104 induces IL-6 and spinal Ca 2+ signaling [10].…”

Section: Discussionmentioning

confidence: 99%

Spinal activity of interleukin 6 mediates myelin basic protein-induced allodynia

Eddinger

Angert

et al. 2016

Brain, Behavior, and Immunity

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Mechanosensory fibers are enveloped by myelin, a unique multilamellar membrane permitting salutatory neuronal conduction. Damage to myelin is thought to contribute to severe pain evoked by innocuous tactile stimulation (i.e. mechanical allodynia). Our earlier (Liu et al, J. Neuroinflammation, 9 (1): 119, 2012) and present data demonstrate that a single injection of a myelin basic protein-derived peptide (MBP84–104) into an intact sciatic nerve produces a robust and long-lasting (>30 days) mechanical allodynia in female rats. The MBP84-104 peptide represents the immunodominant epitope and requires T cells to maintain allodynia. Surprisingly, only systemic gabapentin (a ligand of voltage-gated calcium channel α2δ1), but not ketorolac (COX inhibitor), lidocaine (sodium channel blocker) or MK801 (NMDA antagonist) reverse allodynia induced by the intrasciatic MBP84-104. The genome-wide transcriptional profiling of the sciatic nerve followed by the bioinformatics analyses of the expression changes identified interleukin (IL)-6 as the major cytokine induced by MBP84-104 in both the control and athymic T cell-deficient nude rats. The intrasciatic MBP84-104 injection resulted in both unilateral allodynia and unilateral IL-6 increase the segmental spinal cord (neurons and astrocytes). An intrathecal delivery of a function-blocking IL-6 antibody reduced the allodynia in part by the transcriptional effects in large-diameter primary afferents in DRG. Our data suggest that MBP regulates IL-6 expression in the nervous system and that the spinal IL-6 activity mediates nociceptive processing stimulated by the MBP epitopes released after damage or disease of the somatosensory nervous system.

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“…The potential role of lipid components in APP proteolytic processing has been extensively reviewed ( 100 ); Aβ production is modulated by sphingolipids. Demyelination leads to a release of myelin proteins ( 101 ): Nogo, myelin-associated glycoprotein, and oligodendrocyte myelin glycoprotein inhibit neuronal regeneration via Nogo and PirB receptors ( 102 , 103 ), and MBP causes damage since it acts directly on the neuronal membrane ( 104 ). This protein, which has been regarded as one of the antigens for MS, performs many functions: it is involved in Aβ aggregation and inhibits Aβ fibril assembly ( 105 ), which affects Aβ levels.…”

Section: Proteins Involved In App Proteolytic Processing In Demyelinamentioning

confidence: 99%

Amyloid Proteins and Their Role in Multiple Sclerosis. Considerations in the Use of Amyloid-PET Imaging

et al. 2016

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Thioflavin T derivatives are used in positron-emission tomography (PET) studies to detect amyloid protein deposits in patients with Alzheimer disease. These tracers bind extensively to white matter, which suggests that they may be useful in studies of multiple sclerosis (MS), and that proteins resulting from proteolytic processing of the amyloid precursor protein (APP) may contribute to MS. This article reviews data from both clinical and preclinical studies addressing the role of these proteins, whether they are detected in CSF studies or using PET imaging. APP is widely expressed in demyelinated axons and may have a protective effect in MS and in experimental allergic encephalomyelitis in animals. Several mechanisms associated with this increased expression may affect the degree of remyelination in MS. Amyloid-PET imaging may help determine the degree of demyelination and provide information on the molecular changes linked to APP proteolytic processing experienced by patients with MS.

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Myelin Basic Protein Induces Neuron-Specific Toxicity by Directly Damaging the Neuronal Plasma Membrane

Cited by 30 publications

References 85 publications

Aggregation of MBP in chronic demyelination

Aggregation of MBP in chronic demyelination

Spinal activity of interleukin 6 mediates myelin basic protein-induced allodynia

Amyloid Proteins and Their Role in Multiple Sclerosis. Considerations in the Use of Amyloid-PET Imaging

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