Impaired Differentiation of Schwann Cells in Transgenic Mice with Increased<b><i>PMP22</i></b>Gene Dosage

Magyar, Josef P.; Martini, Rudolf; Rülicke, Thomas; Aguzzi, Adriano; Adlkofer, Katrin; Dembić, Zlatko; Zielasek, Jürgen; Toyka, Klaus V.; Suter, Ueli

doi:10.1523/jneurosci.16-17-05351.1996

Cited by 229 publications

(160 citation statements)

References 56 publications

(56 reference statements)

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“…Although controversial, the altered PMP22 gene dosage in CMT1A appears to be reflected by increased levels of PMP22 mRNA in Schwann cells (Yoshikawa, 1994) and PMP22 protein in peripheral myelin (Vallat, 1996; see also Hanemann, 1994). In mouse models alone, altered dosage of normal myelin genes causing myelination defects has now been described for the major compact myelin proteins in both the CNS and PNS, namely for MBP (Shine et al, 1992), P0 (Giese et al, 1992;Martini et al, 1995), PLP (Nave, 1994), and PMP22 (Adlkofer et al, 1996;Magyar et al, 1996;Sereda et al, 1996). In addition, apparent gain of function, as well as dominant negative mutations, has been identified among this group of proteins (Warner et al, 1996).…”

Section: Discussionmentioning

confidence: 99%

Upregulation of the Endosomal-Lysosomal Pathway in the Trembler-J Neuropathy

1997

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A nonconservative leucine to proline mutation in peripheral myelin protein 22 (PMP22) causes the Trembler-J (Tr J ) neuropathy in mice and humans. The expression levels and localization of the PMP22 protein in the Tr J mouse have not been previously determined. The aim of our studies was to reevaluate the extent of myelin deficit in genotyped heterozygous and homozygous animals and to examine how the Tr J mutation alters the normal in vivo post-translational processing of PMP22. Morphological studies show evidence for primary dysmyelination and myelin instability in affected animals. As expected, Western blot analysis indicates that in adult heterozygous Tr J animals, the level of PMP22 is markedly decreased, similar to myelin basic protein and protein zero, whereas myelin-associated glycoprotein is largely unaffected. The decrease in myelin protein expression is associated with an increase in lysosomal biogenesis, suggestive of augmented endocytosis or autophagy. Double-immunolabeling experiments show the accumulation of PMP22 in endosomal/lysosomal structures of Tr J Schwann cells, and chloroquine treatment of nerve segments indicates that the degradation of protein zero, PMP22, and myelin basic protein is augmented in Tr J nerves. These studies suggest that the Tr J mutation alters myelin stability and that the mutant protein is likely degraded via the lysosomal pathway. Key words: peripheral myelin protein 22; Schwann cells; peripheral nervous system; myelin; neuropathy; Trembler-J; endosomal-lysosomal pathway; protein processingThe Trembler (Tr) and Trembler-J (Tr J ) mice are animal models for the human hereditary neuropathy Charcot-Marie-Tooth (CMT) disease, a group of common (1/2500) (Skre, 1974) heterogeneous peripheral neuropathies. In mice, the semidominant and dominantly inherited mutations in the pmp22 gene result in the nonconservative leucine-to-proline (L16P) or glycine-toaspartic acid (G160D) replacements in the PMP22 protein in the Tr J or Tr mouse, respectively (Suter et al., 1992a,b). These mutations are believed to be responsible for the PNS deficits. The majority of human patients with CMT, however, do not have point mutations in the PMP22 gene, but instead harbor a submicroscopic chromosomal duplication on human chromosome 17p11.2-12, which encompasses the PMP22 gene (for review, see Suter and Snipes, 1995a). The similarity of the disease phenotypes, including disease progression, as well as the finding of the identical Tr J single point mutation in a severely affected CMT disease type 1A (CMT1A) family (Valentijn et al., 1992) substantiates the use of these mice as models of human disease and provide a system for elucidating the biology of the PMP22 protein.The ways in which pmp22 mutations perturb myelination are complex, particularly because the function of the PMP22 protein is unknown (for review, see Suter and Snipes, 1995b). Previous morphological studies of the Tr J mouse used the close linkage of the Tr J phenotype to the vestigial tail marker on mouse chromosome 11 to predict the ...

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Section: Discussionmentioning

confidence: 99%

Upregulation of the Endosomal-Lysosomal Pathway in the Trembler-J Neuropathy

1997

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“…Various spontaneous and transgenic rodent strains have revealed that PMP22 is involved in the initial spiralling of myelin in early development, the determination of myelin thickness, and the maintenance of myelin and axons of peripheral nerves (Suter et al, 1992a,b;Adlkofer et al, 1995;Magyar et al, 1996;Sereda et al, 1996). In vitro results further suggest that PMP22 is also involved in the control of Schwann cell proliferation and apoptosis (Fabbretti et al, 1995;Zoidl et al, 1995).…”

Section: Discussionmentioning

confidence: 99%

“…We studied 9 PMP22 ϩ/0 mice at age 375-426 d and 14 PMP22 ϩ/ϩ mice at age 358 -408 d, using previously described techniques (Adlkofer et al, 1995;Magyar et al, 1996). In brief, mice were anesthetized with a neuroleptic/analgesic combination (Hypnorm; Janssen, Beerse, Belgium).…”

Section: Animals and Determination Of Genotypementioning

confidence: 99%

Heterozygous Peripheral Myelin Protein 22-Deficient Mice Are Affected by a Progressive Demyelinating Tomaculous Neuropathy

et al. 1997

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Hereditary neuropathy with liability to pressure palsy (HNPP) is associated with a heterozygous 1.5 megabase deletion on chromosome 17 that includes the peripheral myelin protein (PMP) gene PMP22. We show that heterozygous PMP22 knock-out mice, which carry only one functional pmp22 allele and thus genetically mimic HNPP closely, display similar morphological and electrophysiological features as observed in HNPP nerves. As reported previously, focal hypermyelinating structures called tomacula, the pathological hallmarks of HNPP, develop progressively in young PMP22 ϩ/0 mice. By following the fate of tomacula during aging, we demonstrate now that these mutant animals are also interesting models for examining HNPP disease mechanisms. Subtle electrophysiological abnormalities are detected in PMP22 ϩ/0 mice Ͼ1 year old, and a significant number of abnormally swollen and degenerating tomacula are present. Thinly myelinated axons and supernumerary Schwann cells forming onion bulbs as fingerprints of repeated cycles of demyelination and remyelination are also encountered frequently. Quantitative analyses using electron microscopy on cross sections and light microscopy on single teased nerve fibers suggest that tomacula are intrinsically unstable structures that are prone to degeneration; however, the severity of morphological and electrophysiological abnormalities in PMP22 ϩ/0 mice is variable. These combined findings are reminiscent of the disease progression in HNPP and offer a possible explanation about why some HNPP patients develop a chronic motor and sensory neuropathy later in life that resembles demyelinating forms of Charcot-MarieTooth disease by both morphological and clinical criteria.

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“…Rat CMT1A model and C22 or C3 mouse models with over‐expression of Pmp22 have all developed slowed conduction velocities and dysmyelination 30, 31, 32…”

Section: Rodent Models For Cmt1amentioning

confidence: 99%

Caveats in the Established Understanding of CMT1A

2017

Ann Clin Transl Neurol

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Charcot‐Marie‐Tooth disease type‐1A (CMT1A) is one of the most common types of inherited peripheral nerve diseases. It is caused by the trisomy of chromosome 17p12 (c17p12), a large DNA segment of 1.4 Mb containing PMP22 plus eight other genes. The size of c17p12 is formidable for any cloning technique to manipulate, and thus precludes production of models in vitro and in vivo that can precisely recapitulate the genetic alterations in humans with CMT1A. This limitation and other factors have led to several assumptions, which have yet been carefully scrutinized, serving as key principles in our understanding of the disease. For instance, one extra copy of c17p12 in patients with CMT1A results in a higher gene dosage of PMP22, thereby expected to produce a higher level of PMP22 mRNA/proteins that cause the disease. However, there has been increasing evidence that PMP22 levels are highly variable among patients with CMT1A and may fall into the normal range at a given time point. This raises an alternative mechanism causing the disease by dysregulation of PMP22 expression or excessive fluctuation of PMP22 levels, not the absolute increase of PMP22. This has become a pressing issue since recent clinical trials using ascorbic acid failed to alter the clinical outcome of CMT1A patients, leaving no effective therapy for the disease. In this article, we will discuss how this fundamental issue might be investigated. In addition, several other key issues in CMT1A will be discussed, including potential mechanisms responsible for the uniform slowing of conduction velocities. A clear understanding of these issues could radically change how therapies should be developed against CMT1A.

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Impaired Differentiation of Schwann Cells in Transgenic Mice with IncreasedPMP22Gene Dosage

Cited by 229 publications

References 56 publications

Upregulation of the Endosomal-Lysosomal Pathway in the Trembler-J Neuropathy

Upregulation of the Endosomal-Lysosomal Pathway in the Trembler-J Neuropathy

Heterozygous Peripheral Myelin Protein 22-Deficient Mice Are Affected by a Progressive Demyelinating Tomaculous Neuropathy

Caveats in the Established Understanding of CMT1A

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