Peripheral nerve extracellular matrix remodeling in Charcot-Marie-Tooth type I disease

Palumbo, Camilla; Massa, Roberto; Panico, Maria Beatrice; Muzio, Antonio Di; Sinibaldi, P; Bernardi, Giorgio; Modesti, Andrea

doi:10.1007/s00401-002-0558-0

Cited by 32 publications

(17 citation statements)

References 37 publications

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“…These results point out that collagens are upregulated in the course of CMT1A in animal models, in accordance with previous reports for human and murine CMT (Palumbo et al, ; Robaglia‐Schlupp et al, ). Another report revealed down‐regulation of cDNA of collagen genes in the CMT1A rat (Vigo et al, ).…”

Section: Resultssupporting

confidence: 93%

“…Increased deposition of collagens in peripheral nerves has been described before, in human and murine CMT but also in acquired neuropathies and even in normal aging (Hill, ; Kanda, Tsukagoshi, Oda, Miyamoto, & Tanabe, ; Palumbo et al, ; Robaglia‐Schlupp et al, ). It is considered to be an unspecific response to peripheral nerve degeneration, forming a collagenous reconfiguration of peripheral nerve tissue.…”

Section: Discussionmentioning

confidence: 80%

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Sodium‐dependent Vitamin C transporter 2 deficiency impairs myelination and remyelination after injury: Roles of collagen and demethylation

Röhr

Halfter

Schulz

et al. 2017

Glia

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Peripheral nerve myelination involves rapid production of tightly bound lipid layers requiring cholesterol biosynthesis and myelin protein expression, but also a collagen-containing extracellular matrix providing mechanical stability. In previous studies, we showed a function of ascorbic acid in peripheral nerve myelination and extracellular matrix formation in adult mice. Here, we sought the mechanism of action of ascorbic acid in peripheral nerve myelination using different paradigms of myelination in vivo and in vitro. We found impaired myelination and reduced collagen expression in Sodium-dependent Vitamin C Transporter 2 heterozygous mice (SVCT2 ) during peripheral nerve development and after peripheral nerve injury. In dorsal root ganglion (DRG) explant cultures, hypo-myelination could be rescued by precoating with different collagen types. The activity of the ascorbic acid-dependent demethylating Ten-eleven-translocation (Tet) enzymes was reduced in ascorbic acid deprived and SVCT2 DRG cultures. Further, in ascorbic acid-deprived DRG cultures, methylation of a CpG island in the collagen alpha1 (IV) and alpha2 (IV) bidirectional promoter region was increased compared to wild-type and ascorbic acid treated controls. Taken together, these results provide further evidence for the function of ascorbic acid in myelination and extracellular matrix formation in peripheral nerves and suggest a putative molecular mechanism of ascorbic acid function in Tet-dependent demethylation of collagen promoters.

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Section: Resultssupporting

confidence: 93%

Section: Discussionmentioning

confidence: 80%

Sodium‐dependent Vitamin C transporter 2 deficiency impairs myelination and remyelination after injury: Roles of collagen and demethylation

Röhr

Halfter

Schulz

et al. 2017

Glia

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“…Because the nerves of c-Jun OE/OE nerves are 121,486 μm 2 larger than WT nerves, >95% of the enlargement seen in c-Jun OE/OE nerves is due to increased collagen-containing extracellular space, with a likely contribution from increased number of Remak cells and cells other than Schwann cells. Increase in endoneurial connective tissue is seen in a number of neuropathies, including CMT1A, and in the trembler and twitcher mouse mutants ( Low, 1977 ; Palumbo et al, 2002 ; Ling et al, 2005 ; Kagitani-Shimono et al, 2008 ; Fledrich et al, 2012 ).…”

Section: Resultsmentioning

confidence: 99%

Graded Elevation of c-Jun in Schwann CellsIn Vivo: Gene Dosage Determines Effects on Development, Remyelination, Tumorigenesis, and Hypomyelination

et al. 2017

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Schwann cell c-Jun is implicated in adaptive and maladaptive functions in peripheral nerves. In injured nerves, this transcription factor promotes the repair Schwann cell phenotype and regeneration and promotes Schwann-cell-mediated neurotrophic support in models of peripheral neuropathies. However, c-Jun is associated with tumor formation in some systems, potentially suppresses myelin genes, and has been implicated in demyelinating neuropathies. To clarify these issues and to determine how c-Jun levels determine its function, we have generated c-Jun OE/+ and c-Jun OE/OE mice with graded expression of c-Jun in Schwann cells and examined these lines during development, in adulthood, and after injury using RNA sequencing analysis, quantitative electron microscopic morphometry, Western blotting, and functional tests. Schwann cells are remarkably tolerant of elevated c-Jun because the nerves of c-Jun OE/+ mice, in which c-Jun is elevated ∼6-fold, are normal with the exception of modestly reduced myelin thickness. The stronger elevation of c-Jun in c-Jun OE/OE mice is, however, sufficient to induce significant hypomyelination pathology, implicating c-Jun as a potential player in demyelinating neuropathies. The tumor suppressor P19ARF is strongly activated in the nerves of these mice and, even in aged c-Jun OE/OE mice, there is no evidence of tumors. This is consistent with the fact that tumors do not form in injured nerves, although they contain proliferating Schwann cells with strikingly elevated c-Jun. Furthermore, in crushed nerves of c-Jun OE/+ mice, where c-Jun levels are overexpressed sufficiently to accelerate axonal regeneration, myelination and function are restored after injury.SIGNIFICANCE STATEMENT In injured and diseased nerves, the transcription factor c-Jun in Schwann cells is elevated and variously implicated in controlling beneficial or adverse functions, including trophic Schwann cell support for neurons, promotion of regeneration, tumorigenesis, and suppression of myelination. To analyze the functions of c-Jun, we have used transgenic mice with graded elevation of Schwann cell c-Jun. We show that high c-Jun elevation is a potential pathogenic mechanism because it inhibits myelination. Conversely, we did not find a link between c-Jun elevation and tumorigenesis. Modest c-Jun elevation, which is beneficial for regeneration, is well tolerated during Schwann cell development and in the adult and is compatible with restoration of myelination and nerve function after injury.

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“…Structural abnormalities of the node may underlie the changes in the excitability in motor axons of patients with hereditary neuropathy with liability to pressure palsies (Jankelowitz and Burke, 2013). In addition, remodeling of the nodal ECM occurs in CMT type 1 pathology: tenascin, normally accumulated at the nodal ECM, was displaced and extended along the internodes in sural nerves from patients with CMT type 1 (Palumbo et al, 2002). These changes in the nodal ECM may affect nerve conduction, because the ECM, including tenascin, has been suggested to serve as an extracellular Na + reservoir in the perinodal space [reviewed in (Poliak and Peles, 2003)].…”

Section: Nodal Dysfunction/disruption In Neurological Diseasesmentioning

confidence: 99%

Node of Ranvier Disruption as a Cause of Neurological Diseases

Susuki

2013

ASN Neuro

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Dysfunction and/or disruption of nodes of Ranvier are now recognized as key contributors to the pathophysiology of various neurological diseases. One reason is that the excitable nodal axolemma contains a high density of Nav (voltage-gated Na+ channels) that are required for the rapid and efficient saltatory conduction of action potentials. Nodal physiology is disturbed by altered function, localization, and expression of voltage-gated ion channels clustered at nodes and juxtaparanodes, and by disrupted axon–glial interactions at paranodes. This paper reviews recent discoveries in molecular/cellular neuroscience, genetics, immunology, and neurology that highlight the critical roles of nodes of Ranvier in health and disease.

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Peripheral nerve extracellular matrix remodeling in Charcot-Marie-Tooth type I disease

Cited by 32 publications

References 37 publications

Sodium‐dependent Vitamin C transporter 2 deficiency impairs myelination and remyelination after injury: Roles of collagen and demethylation

Sodium‐dependent Vitamin C transporter 2 deficiency impairs myelination and remyelination after injury: Roles of collagen and demethylation

Graded Elevation of c-Jun in Schwann CellsIn Vivo: Gene Dosage Determines Effects on Development, Remyelination, Tumorigenesis, and Hypomyelination

Node of Ranvier Disruption as a Cause of Neurological Diseases

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