Gain of glycosylation: A new pathomechanism of myelin protein zero mutations

Prada, Valeria; Passalacqua, Mario; Bono, Marı́a Rosa; Luzzi, Paola; Scazzola, Sara; Nobbio, Lucilla; Capponi, Simona; Bellone, Emilia; Mandich, Paola; Mancardi, Gianluigi; Shy, Michael E.; Schenone, Angelo; Grandis, Marina

doi:10.1002/ana.22695

Cited by 24 publications

(30 citation statements)

References 24 publications

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“…Moreover, many prior reports have outlined other potential pathogenic mechanisms including disruption of compaction,27 myelin packing,28 signaling from the cytoplasmic domain,29 disruption of adhesion,2 or disruption of glycosylation 30. Therefore, we recognize that UPR activation by itself cannot be the sole cause of the phenotypes of CMT1B and that these other mechanisms likely participate as well.…”

Section: Discussionmentioning

confidence: 87%

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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Section: Discussionmentioning

confidence: 87%

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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“…Different types of mutations, even those affecting the very same amino acid, result in different neuropathies, ranging from dys/demyelinating CMT1B/DSS/CH diseases to axonal CMT2 (Shy, 2006; Timmerman et al, 2014; Sanmaneechai et al, 2015). A subset of P0 mutations associated with altered P0 trafficking have been described, among which the best characterized are the R98C and S63del mutations in the extracellular domain of P0 (P0-ECD) (Figure 3B and Table 1; Shames et al, 2003; Khajavi et al, 2005; Wrabetz et al, 2006; Grandis et al, 2008; Prada et al, 2012; Saporta et al, 2012). In humans the R98C mutation results in severe early onset dysmyelinating and demyelinating neuropathy, partially recapitulated in R98C knock-in mice (Gabreëls-Festen et al, 1996; Bai et al, 2006; Saporta et al, 2012).…”

Section: Erqc and Charcot-marie-tooth (Cmt) Neuropathiesmentioning

confidence: 99%

Endoplasmic Reticulum Protein Quality Control Failure in Myelin Disorders

Volpi¹,

Touvier²,

D’Antonio³

2017

Front. Mol. Neurosci.

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Reaching the correct three-dimensional structure is crucial for the proper function of a protein. The endoplasmic reticulum (ER) is the organelle where secreted and transmembrane proteins are synthesized and folded. To guarantee high fidelity of protein synthesis and maturation in the ER, cells have evolved ER-protein quality control (ERQC) systems, which assist protein folding and promptly degrade aberrant gene products. Only correctly folded proteins that pass ERQC checkpoints are allowed to exit the ER and reach their final destination. Misfolded glycoproteins are detected and targeted for degradation by the proteasome in a process known as endoplasmic reticulum-associated degradation (ERAD). The excess of unstructured proteins in the ER triggers an adaptive signal transduction pathway, called unfolded protein response (UPR), which in turn potentiates ERQC activities in order to reduce the levels of aberrant molecules. When the situation cannot be restored, the UPR drives cells to apoptosis. Myelin-forming cells of the central and peripheral nervous system (oligodendrocytes and Schwann cells) synthesize a large amount of myelin proteins and lipids and therefore are particularly susceptible to ERQC failure. Indeed, deficits in ERQC and activation of ER stress/UPR have been implicated in several myelin disorders, such as Pelizaeus-Merzbacher and Krabbe leucodystrophies, vanishing white matter disease and Charcot-Marie-Tooth neuropathies. Here we discuss recent evidence underlying the importance of proper ERQC functions in genetic disorders of myelinating glia.

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“…Tools to study site-specific glycosylation (glycoproteomics) have matured over the last decade allowing analysis of site-specific glycan structures in brain glycoconjugates. Gain-of-glycosylation can also occur (Prada et al, 2012). It is also possible that alterations in glycosylation may arise indirectly from changes in cell metabolism or in the organization of cellular glycosylation machinery in the ER and Golgi.…”

Section: Glycogenes As Risk Factors For Asdsmentioning

confidence: 99%

Glycan susceptibility factors in autism spectrum disorders

Dwyer

2016

Molecular Aspects of Medicine

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Idiopathic autism spectrum disorders (ASDs) are neurodevelopmental disorders with unknown etiology. An estimated 1:68 children in the U.S. are diagnosed with ASDs, making these disorders a substantial public health issue. Recent advances in genome sequencing have identified numerous genetic variants across the ASD patient population. Many genetic variants identified occur in genes that encode glycosylated extracellular proteins (proteoglycans or glycoproteins) or enzymes involved in glycosylation (glycosyltransferases and sulfotransferases). It remains unknown whether “glycogene” variants cause changes in glycosylation and whether they contribute to the etiology and pathogenesis of ASDs. Insights into glycan susceptibility factors are provided by studies in the normal brain and congenital disorders of glycosylation, which are often accompanied by ASD-like behaviors. The purpose of this review is to present evidence that supports a contribution of extracellular glycans and glycoconjugates to the etiology and pathogenesis of idiopathic ASDs and other types of pervasive neurodevelopmental disorders.

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Gain of glycosylation: A new pathomechanism of myelin protein zero mutations

Cited by 24 publications

References 24 publications

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

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

Endoplasmic Reticulum Protein Quality Control Failure in Myelin Disorders

Glycan susceptibility factors in autism spectrum disorders

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