Identification of a New Pmp22 Mouse Mutant and Trafficking Analysis of a Pmp22 Allelic Series Suggesting That Protein Aggregates May Be Protective in Pmp22-Associated Peripheral Neuropathy

Isaacs, Adrian M.; Jeans, Alexander; Oliver, Peter L.; Vizor, Lucie; Brown, Steve; Hunter, A. Jackie; Davies, Kay E.

doi:10.1006/mcne.2002.1158

Cited by 35 publications

(30 citation statements)

References 32 publications

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“…Generally, the neuropathic features associated with these point mutations are more severe than those accompanying the gene duplication or deletion genotypes. The molecular bases underlying this trend are unknown, yet impaired trafficking (Sanders et al, 2001), interactions between the Wt and mutant protein (Tobler et al, 2002), and formation of aggregates (Isaacs et al, 2002;Fortun et al, 2003) have been suggested to play roles. Here we describe the main subcellular events associated with two independent frameshift mutations at position G94 that are associated with severe CMT1A or HNPP.…”

Section: Discussionmentioning

confidence: 99%

“…This difference in the potential for aggregation is supported by the higher detergent insolubility of the extended, compared with the truncated, protein. Based on the correlation with less severe disease phenotypes (Isaacs et al, 2002) and the existence of an autophagy-dependent aggregate clearance mechanism (Fortun et al, 2003), a protective role for the formation of PMP22 aggregates has been proposed. The correlation between aggregates (G94fsX222-HA) and the least severe neuropathy (HNPP) presented here supports the hypothetical protective role of PMP22 aggresomes.…”

Section: Discussionmentioning

confidence: 99%

“…The Wt-PMP22 is a substrate of the proteasome, and 80% of the newly synthesized protein is rapidly degraded (Pareek et al, 1997;Ryan et al, 2002). The turnover rates of certain mutated PMP22s are reduced, which is associated with the formation of perinuclear protein aggregates, termed aggresomes, and impairment of proteasome activity (Notterpek et al, 1999b;Ryan et al, 2002;Isaacs et al, 2002;Fortun et al, 2003Fortun et al, , 2005. Another mechanism by which mutated PMP22s may affect SC function is by altering cell proliferation (Zoidl et al, 1997).…”

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confidence: 99%

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Molecular alterations resulting from frameshift mutations in peripheral myelin protein 22: Implications for neuropathy severity

Johnson

Roux

Fletcher

et al. 2005

J of Neuroscience Research

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Alterations in peripheral myelin protein 22 (PMP22) expression are associated with a heterogeneous group of hereditary demyelinating peripheral neuropathies. Two mutations at glycine 94, a single guanine insertion or deletion in PMP22, result in different reading frameshifts and, consequently, an extended G94fsX222 or a truncated G94fsX110 protein, respectively. Both of these autosomal dominant mutations alter the second half of PMP22 and yet are linked to clinical phenotypes with distinct severities. The G94fsX222 is associated with hereditary neuropathy with liability to pressure palsies, whereas G94fsX110 causes severe neuropathy diagnosed as Dejerine-Sottas disease or Charcot-Marie-Tooth disease type IA. To investigate the subcellular changes associated with the G94 frameshift mutations, we expressed epitope-tagged forms in primary rat Schwann cells. Biochemical and immunolabeling studies indicate that, unlike the wild-type protein, which is targeted for the plasma membrane, frameshift PMP22s are retained in the cell, prior to reaching the medial Golgi compartment. Similar to Wt-PMP22, both frameshift mutants are targeted for proteasomal degradation and accumulate in detergent-insoluble, ubiquitin-containing aggregates upon inhibition of this pathway. The extended frameshift PMP22 shows the ability to form spontaneous aggregates in the absence of proteasome inhibition. On the other hand, Schwann cells expressing the truncated protein proliferate at a significantly higher rate than Schwann cells expressing the wild-type or the extended PMP22. In summary, these results suggest that a greater potential for PMP22 aggregation is associated with a less severe phenotype, whereas dysregulation of Schwann cell proliferation is linked to severe neuropathy.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Molecular alterations resulting from frameshift mutations in peripheral myelin protein 22: Implications for neuropathy severity

Johnson

Roux

Fletcher

et al. 2005

J of Neuroscience Research

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“…Recently, nerve conduction and histological studies have shown that Tre-J mice may represent a model of severe CMT1A disease [90,91] . In a large-scale N-ethyl-N-nitrosourea mutagenesis project, 3 new PMP22 mouse mu-tants (Tre-m1H, Tre-m2H and Tre-m3H) have been identified; they all exhibit a CMT phenotype [92,93] . Interestingly the first strain has a mutation at the same amino acid found in a DSS family.…”

Section: Animal Models Of Inherited Neuropathiesmentioning

confidence: 99%

Evaluation Tools and Animal Models of Peripheral Neuropathies

Fricker

Muller²,

Frydman³

2008

Neurodegener Dis

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Peripheral neuropathies are common and frequently debilitating disorders linked to degeneration of peripheral nerves that supply mainly the distal muscles of the extremities. Due to the diverse origin of the pathology (genetic, systemic or environmental), peripheral neuropathies exhibit different clinical forms: acute or chronic, symmetrical or asymmetrical, demyelinating or axonal. In the last 30 years, to gain insight into cellular and molecular mechanisms underlying neuropathies, numerous animal models – either spontaneous or induced by chemical compounds, physical injury or genetic engineering – have been extensively developed and used. In this review, we present (1) the methods used to assess the peripheral neuropathies in the major available animal models and their main pathological characteristics and (2) the main models and their relevance to the human pathology, and, consequently, their usefulness for preclinical studies. Finally, we discuss the emerging, recently developed tools, that should allow to gain a better insight into the mechanisms underlying the peripheral neuropathies.

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“…One disesease mechanism has been elucidated in that some PMP22 mutant proteins are retained intracellularly, in the endoplasmic reticulum (ER) and/or the intermediate compartment [38, 61, 64, 69, 76 -80]. In addition, the mutant proteins encoded by the Tr (G150D) and Tr-J alleles (L16P) aggregate abnormally in transfected fibroblasts [70], although such aggregates have been suggested to be even protective in PMP22 point mutation-based peripheral neuropathies [52]. Since PMP22 forms dimers and multimers, mutant PMP22 retained in the ER and/or intermediate compartment may prevent the efficient transport of wild-type PMP22 to the cell membrane in the form of a classical dominant-negative effect [38,70,80].…”

Section: Genes Mutated In Cmtmentioning

confidence: 99%

The causes of Charcot-Marie-Tooth disease

Young

Suter

2003

Cellular and Molecular Life Sciences (CMLS)

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Charcot-Marie-Tooth (CMT) disease serves as the summary term for the most frequent forms of inherited peripheral neuropathies that affect motor and sensory nerves. In the last 12 years, 14 genes have been identified that cause different CMT subforms. The genes found initially are predominantly responsible for demyelinating and dysmyelinating neuropathies. Genes affected in axonal and rare forms of CMT have only recently been identified. In this review, we will focus on the currently known genes that are associated with CMT syndromes with regards to their genetics and function.

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Identification of a New Pmp22 Mouse Mutant and Trafficking Analysis of a Pmp22 Allelic Series Suggesting That Protein Aggregates May Be Protective in Pmp22-Associated Peripheral Neuropathy

Cited by 35 publications

References 32 publications

Molecular alterations resulting from frameshift mutations in peripheral myelin protein 22: Implications for neuropathy severity

Molecular alterations resulting from frameshift mutations in peripheral myelin protein 22: Implications for neuropathy severity

Evaluation Tools and Animal Models of Peripheral Neuropathies

The causes of Charcot-Marie-Tooth disease

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