Mice with a deletion of the major central myelin protein exhibit hypersensitivity to noxious thermal stimuli: involvement of central sensitization

Petit, Bérengère; Giraudet, Fabrice; Béchon, Céline; Bardin, Laurent; Avan, Paul; Boespflug‐Tanguy, Odile; Bégou, Mélina

doi:10.1016/j.nbd.2014.01.005

Cited by 15 publications

(12 citation statements)

References 44 publications

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“…The main consequence of PLP‐deficiency is axonal degeneration, as observed in SPG2 patients and Plp null mice (de Monasterio‐Schrader et al, ; Edgar, McLaughlin, Yool, et al, ; Garbern et al, ; Griffiths et al, ; Gruenenfelder, Thomson, Penderis, & Edgar, ; Petit et al, ). Here, we have genetically tested whether neuronal or oligodendroglial dysfunction is the primary cause of axonal impairment caused by loss‐of‐function mutations affecting the Plp gene.…”

Section: Discussionmentioning

confidence: 99%

Genetic dissection of oligodendroglial and neuronalPlp1function in a novel mouse model of spastic paraplegia type 2

Lüders

Patzig

Simons

et al. 2017

Glia

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Proteolipid protein (PLP) is the most abundant integral membrane protein in compact central nervous system myelin, and null mutations of the PLP1 gene cause spastic paraplegia type 2 (SPG2). SPG2 patients and PLP-deficient mice exhibit only moderate abnormalities of myelin but progressive degeneration of long axons. Since Plp1 gene products are detected in a subset of neurons it has been suggested that the loss of neuronal Plp1 expression could be the cause of the axonal pathology. To test this hypothesis, we created mice with a floxed Plp1 allele for selective Cre-mediated recombination in neurons. We find that recombination of Plp1 in excitatory projection neurons does not cause neuropathology, whereas oligodendroglial targeting of Plp1 is sufficient to cause the entire neurodegenerative spectrum of SPG2 including axonopathy and secondary neuroinflammation. We conclude that PLP-dependent loss of oligodendroglial support is the primary cause of axonal degeneration in SPG2.

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Section: Discussionmentioning

confidence: 99%

Genetic dissection of oligodendroglial and neuronalPlp1function in a novel mouse model of spastic paraplegia type 2

Lüders

Patzig

Simons

et al. 2017

Glia

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“…We note that connexin 32 (Cx32), the product of the GJB1‐ gene causative of X‐linked CMT, also has an early supportive role for peripheral axons (Vavlitou et al, ). However, Cx32 null mice develop a full‐blown neuropathy with strong neuroinflammation (Groh et al, ; Klein et al, ), whereas peripheral nerves of Plp null mice display only infrequent neuropathic changes even at higher age (Petit et al, ). Yet, the contribution of PLP to the support of peripheral axons appears moderate compared with the CNS, in which axonal degeneration is the main consequence of PLP‐deficiency as observed in SPG2 patients and Plp null mice (de Monasterio‐Schrader et al, ; Edgar and Nave, ; Griffiths et al, ; Saugier‐Veber et al, ).…”

Section: Discussionmentioning

confidence: 99%

Proteolipid protein modulates preservation of peripheral axons and premature death when myelin protein zero is lacking

Patzig

Kusch

Fledrich

et al. 2015

Glia

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Protein zero (P0) is the major structural component of peripheral myelin. Lack of this adhesion protein from Schwann cells causes a severe dysmyelinating neuropathy with secondary axonal degeneration in humans with the neuropathy Dejerine-Sottas syndrome (DSS) and in the corresponding mouse model (P0(null)-mice). In the mammalian CNS, the tetraspan-membrane protein PLP is the major structural myelin constituent and required for the long-term preservation of myelinated axons, which fails in hereditary spastic paraplegia (SPG type-2) and the relevant mouse model (Plp(null)-mice). The Plp-gene is also expressed in Schwann cells but PLP is of very low abundance in normal peripheral myelin; its function has thus remained enigmatic. Here we show that the abundance of PLP but not of other tetraspan myelin proteins is strongly increased in compact peripheral myelin of P0(null)-mice. To determine the functional relevance of PLP expression in the absence of P0, we generated P0(null)*Plp(null)-double-mutant mice. Compared with either single-mutant, P0(null)*Plp(null)-mice display impaired nerve conduction, reduced motor functions, and premature death. At the morphological level, axonal segments were frequently non-myelinated but in a one-to-one relationship with a hypertrophic Schwann cell. Importantly, axonal numbers were reduced in the vital phrenic nerve of P0(null)*Plp(null)-mice. In the absence of P0, thus, PLP also contributes to myelination by Schwann cells and to the preservation of peripheral axons. These data provide a link between the Schwann cell-dependent support of peripheral axons and the oligodendrocyte-dependent support of central axons.

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“…The in vivo approach allowed the acquisition of electroneuromyographic recordings in a noninvasive manner as described previously (Petit et al ., 2014). Briefly, 5–6 mice per group were anesthetized with a mixture of ketamine (75 mg kg −1 ; Imalgene ® , Merial, France) and medetomidine (1 mg kg −1 ; Dormitor ® , Pfizer, New York, NY, USA) i.p.…”

Section: Methodsmentioning

confidence: 99%

Absence of Tau triggers age‐dependent sciatic nerve morphofunctional deficits and motor impairment

Lopes

Pinto

et al. 2016

Aging Cell

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SummaryDementia is the cardinal feature of Alzheimer's disease (AD), yet the clinical symptoms of this disorder also include a marked loss of motor function. Tau abnormal hyperphosphorylation and malfunction are well‐established key events in AD neuropathology but the impact of the loss of normal Tau function in neuronal degeneration and subsequent behavioral deficits is still debated. While Tau reduction has been increasingly suggested as therapeutic strategy against neurodegeneration, particularly in AD, there is controversial evidence about whether loss of Tau progressively impacts on motor function arguing about damage of CNS motor components. Using a variety of motor‐related tests, we herein provide evidence of an age‐dependent motor impairment in Tau−/− animals that is accompanied by ultrastructural and functional impairments of the efferent fibers that convey motor‐related information. Specifically, we show that the sciatic nerve of old (17–22‐months) Tau−/− mice displays increased degenerating myelinated fibers and diminished conduction properties, as compared to age‐matched wild‐type (Tau+/+) littermates and younger (4–6 months) Tau−/− and Tau+/+ mice. In addition, the sciatic nerves of Tau−/− mice exhibit a progressive hypomyelination (assessed by g‐ratio) specifically affecting large‐diameter, motor‐related axons in old animals. These findings suggest that loss of Tau protein may progressively impact on peripheral motor system.

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Mice with a deletion of the major central myelin protein exhibit hypersensitivity to noxious thermal stimuli: involvement of central sensitization

Cited by 15 publications

References 44 publications

Genetic dissection of oligodendroglial and neuronalPlp1function in a novel mouse model of spastic paraplegia type 2

Genetic dissection of oligodendroglial and neuronalPlp1function in a novel mouse model of spastic paraplegia type 2

Proteolipid protein modulates preservation of peripheral axons and premature death when myelin protein zero is lacking

Absence of Tau triggers age‐dependent sciatic nerve morphofunctional deficits and motor impairment

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