Different Intracellular Pathomechanisms Produce Diverse<i>Myelin Protein Zero</i>Neuropathies in Transgenic Mice

Wrabetz, Lawrence; D’Antonio, Maurizio; Pennuto, Maria; Dati, Gabriele; Tinelli, Elisa; Fratta, Pietro; Previtali, Stefano C.; Imperiale, Daniele; Zielasek, Jürgen; Toyka, Klaus V.; Avila, Robin; Kirschner, Daniel A.; Messing, Albee; Feltri, M. Laura; Quattrini, Angelo

doi:10.1523/jneurosci.3819-05.2006

Cited by 144 publications

(284 citation statements)

References 51 publications

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“…At 4 mo, the expression of MpzS63del is lower, similar to endogenous Mpz, (Feltri et al, 1999), even though demyelinating neuropathy becomes more evident in S63del nerves (Wrabetz et al, 2006), similar to patients with MPZS63del, in whom neuropathy appears gradually over the first two decades of life (Miller et al, 2012). Accordingly, transcriptomic analysis showed that the majority of the up-regulated genes were related to inflammation, a typical consequence of demyelinating neuropathy.…”

Section: P0s63del Activates a Robust Stress Response In Transgenic Micementioning

confidence: 76%

“…We observed that P0S63del extensively perturbs gene expression following on the expression of the Mpz-based S63del transgene ( Fig. 1 B); in fact, as early as P5, when the transgene is already robustly expressed (Feltri et al, 1999;Wrabetz et al, 2006), 771 genes were found to vary (increased or decreased) by >1.5-fold compared with WT; this number rose to 1,205 genes at P28, when myelination peaks, and decreased to 324 genes at 4 mo, when myelin genes, and thus the MpzS63del transgene, are expressed at lower levels (Wrabetz et al, 2006).…”

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confidence: 87%

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Resetting translational homeostasis restores myelination in Charcot-Marie-Tooth disease type 1B mice

D’Antonio¹,

Musner²,

Scapin³

et al. 2013

J Cell Biol

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Section: P0s63del Activates a Robust Stress Response In Transgenic Micementioning

confidence: 76%

mentioning

confidence: 87%

Resetting translational homeostasis restores myelination in Charcot-Marie-Tooth disease type 1B mice

D’Antonio¹,

Musner²,

Scapin³

et al. 2013

J Cell Biol

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“…S8A) nor in mature nerves (P56, periodicity of mutant vs. wt: 131.7 Ϯ 2.8 Å vs. 132.2 Ϯ 1.6 Å). To accurately measure myelin period and membrane packing, we analyzed the internodal myelin of unfixed late adult mutants by using X-ray diffraction (XRD) (17,18). The relative amount of mutant myelin in sciatic nerve was close to one-half (0.57) of wild-type myelin at P210, due to a reduction in average myelin sheath thickness, whereas no differences were found for the optic nerve (Fig.…”

Section: Scap Deletion Causes a Loss Of Srebp-mediated Gene Expressionmentioning

confidence: 99%

SCAP is required for timely and proper myelin membrane synthesis

Verheijen

Camargo

Verdier

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

103

111

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lipid metabolism ͉ neuron-glia interactions ͉ neuropathy ͉ X-ray diffraction T he rapid saltatory conduction of neuronal action potentials is crucially dependent on the insulating myelin membrane, an organelle synthesized by Schwann cells in the PNS, and by oligodendrocytes in the CNS (1). The electrical insulating property of the myelin membrane is provided by its high and characteristic lipid content with high levels of cholesterol, galactosphingolipids, and saturated long-chain fatty acids (1). Accordingly, metabolic disorders of cholesterol [e.g., Smith-Lemli-Opitz-syndrome and Tangier disease (2, 3)], galactosphingolipids (4, 5), or of fatty acid metabolism [Refsum's disease and diabetes mellitus (2)] often produce myelin defects.With the Schwann cell membrane surface area expanding a spectacular 6,500-fold during myelination (6), it is obvious that production of myelin membrane requires a large amount and diversity of myelin proteins and lipids. Myelination of peripheral nerves is a highly dynamic process with an acute phase that peaks in the second postnatal week in the mouse and a phase of steady-state maintenance in adult nerves (7). While it has been suggested that many of the myelin lipids are synthesized in the nerve itself, as was demonstrated for cholesterol (8, 9), the factors regulating their synthesis in myelinating Schwann cells are largely unknown. We recently profiled transcription in the peripheral nerve during myelination and found that sterol regulatory elementbinding proteins (SREBPs) are highly expressed in myelinating Schwann cells (10)(11)(12). SREBPs, consisting of SREBP-1a, SREBP1c, and SREBP-2, belong to the family of basic helix-loop-helixleucine zipper (bHLH-Zip) transcription factors that regulate lipid metabolism. SREBP-1c and SREBP-2 preferentially govern the transcriptional activation of genes involved in fatty acid and cholesterol metabolism, respectively, whereas SREBP-1a activates both pathways (13). SREBP transcription factors crucially rely on post-translational activation involving the sterol sensor SCAP. When sterol levels are low, SCAP escorts the SREBPs from the ER to the Golgi, where they are activated by processing through the membrane-associated proteases, S1P and S2P. The resulting mature and transcriptionally active forms of the SREBPs translocate to the nucleus where they bind genes containing sterol regulatory elements (13,14).Here, we determined the role of SCAP in myelination by its conditional ablation in Schwann cells. We found that deletion of SCAP seriously affected the dynamics of myelin membrane synthesis and caused neuropathy. However, these phenotypes improved with aging; SCAP mutant Schwann cells were able to slowly synthesize myelin, in an external lipid-dependent fashion, resulting in myelin membrane defects that are associated with abnormal lipid composition. Our data demonstrated the crucial role of SCAPmediated control of cholesterol and lipid metabolism necessary for production of a proper myelin membrane by Schwann cells.

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“…However, several mutations cause the mutant protein to be retained in the endoplasmic reticulum (ER) rather than being transported to the cell membrane or myelin sheath. Examples include in vitro studies of MpzSer51delTrp57,2 506delT and 550del3insG3 and in vivo reports of Ser63del and Arg98Cys MPZ mice 4, 5, 6. ER retention in both mouse models activated a canonical unfolded protein response (UPR) 4, 5.…”

Section: Introductionmentioning

confidence: 99%

Myelin protein zero mutations and the unfolded protein response in Charcot Marie Tooth disease type 1B

Bai

Brennan

et al. 2018

Ann Clin Transl Neurol

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ObjectiveTo determine the prevalence of MPZ mutations that cause Charcot Marie Tooth neuropathy type 1B (CMT1B) and activate the unfolded protein Response (UPR).Background CMT1B is caused by >200 heterozygous mutations in MPZ, the major protein in peripheral nerve myelin. Mutations Ser63del MPZ and Arg98Cys MPZ cause the mutant protein to be retained in the ER and activate the generally adaptive UPR. Treatments that modulate UPR activation have improved cellular and rodent models of CMT1B raising the possibility that other MPZ mutations that activate the UPR would also respond favorably to similar treatment. The prevalence of MPZ mutations that activate the UPR is unknown.MethodsWe developed a dual luciferase reporter assay of Xbp1 splicing using stably transfected RT4 Schwann cells to assay the ability of cDNA constructs bearing 46 distinct MPZ mutations to activate the UPR. Constructs also carried an HA tag to permit detection of ER retention of mutant proteins. UPR activation and ER retention were correlated with clinical phenotypes.ResultsEighteen mutations demonstrated ER retention and UPR activation to a similar degree as Ser63del and Arg98Cys MPZ. Thirty‐five of the mutations activated the UPR > 1.5 fold compared to that of wild‐type MPZ. Correlation was high between firefly and Nano‐luciferase reporters and between both reporters and ER localization. UPR activity did not correlate with clinical onset or severity.ConclusionMany CMT1B causing mutations activate the UPR and may be susceptible to therapeutic efforts to facilitate UPR function.

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Different Intracellular Pathomechanisms Produce DiverseMyelin Protein ZeroNeuropathies in Transgenic Mice

Cited by 144 publications

References 51 publications

Resetting translational homeostasis restores myelination in Charcot-Marie-Tooth disease type 1B mice

Resetting translational homeostasis restores myelination in Charcot-Marie-Tooth disease type 1B mice

SCAP is required for timely and proper myelin membrane synthesis

Myelin protein zero mutations and the unfolded protein response in Charcot Marie Tooth disease type 1B

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