A molecular basis for hereditary motor and sensory neuropathy disorders

Shy, Michael E.; Balsamo, Janne; Lilien, Jack; Kamholz, John

doi:10.1007/s11910-001-0079-6

Cited by 11 publications

(9 citation statements)

References 96 publications

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“…Like PMP22, MPZ is a major structural protein (>50% of all PNS myelin proteins) specific to compact myelin in the PNS (Shy et al, 2001). Deficiency of MPZ would be expected to negatively affect myelin stability.…”

Section: Resultsmentioning

confidence: 99%

Conduction Block in PMP22 Deficiency

et al. 2010

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Patients with PMP22 deficiency present with focal sensory and motor deficits when peripheral nerves are stressed by mechanical force. It has been hypothesized that these focal deficits are due to mechanically induced conduction block (CB). To test this hypothesis, we induced 60-70% CB (defined by electrophysiological criteria) by nerve compression in an authentic mouse model of HNPP with an inactivation of one of the two pmp22 alleles (pmp22+/−). Induction time for the CB was significantly shorter in pmp22+/− mice than that in pmp22+/+ mice. This shortened induction was not found in the mice with deficiency of myelin protein zero (MPZ), a major structural protein of compact myelin. Pmp22+/− nerves showed intact tomacula with no segmental demyelination in both non-compressed and compressed conditions, normal molecular architecture, and normal concentration of voltage-gated sodium channels by H3-saxitoxin binding assay. However, focal constrictions were observed in the axonal segments enclosed by tomacula, a pathological hallmark of HNPP. The constricted axons increase axial-resistance to action potential propagation, which should hasten the induction of CB in pmp22 deficiency. Taken together, these results demonstrate that a function of Pmp22 is to protect the nerve from mechanical injury.

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Section: Resultsmentioning

confidence: 99%

Conduction Block in PMP22 Deficiency

et al. 2010

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“…In primary demyelinating forms, myelin formation or maintenance is impaired, leading to decreased nerve conduction velocities, invariably followed by axonal loss at later stages. In intermediate forms, a mild nerve conduction velocity reduction and reduced compound muscle action potential amplitudes are detectable simultaneously, indicative of a synchronous impairment of the myelin-axonal entity (Shy et al , 2001; Suter and Scherer, 2003). Only a few Charcot–Marie–Tooth disease forms are caused by mutations in genes that are exclusively or mainly expressed in peripheral nerves, raising the question of why mutations in Charcot–Marie–Tooth disease-linked genes specifically damage peripheral nerves (Berger et al , 2006; Niemann et al , 2006).…”

Section: Introductionmentioning

confidence: 99%

The Gdap1 knockout mouse mechanistically links redox control to Charcot–Marie–Tooth disease

Niemann¹,

Huber²,

Wagner³

et al. 2014

Brain

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“…During the last ten years there have been many advances with the molecular diagnosis of CMT neuropathies, however effective drug therapy is still not available (Pareyson and Marchesi, 2009). Duplications of, or point mutations within, the Peripheral Myelin Protein 22 ( PMP22 ) gene are known to cause CMT1A (Shy et al, 2001) and other related neuropathies. PMP22 is a hydrophobic integral membrane glycoprotein that is mostly expressed by myelinating Schwann cells (SCs) (Naef and Suter, 1998).…”

Section: Introductionmentioning

confidence: 99%

Rapamycin Activates Autophagy and Improves Myelination in Explant Cultures from Neuropathic Mice

Rangaraju¹,

Verrier²,

Madorsky³

et al. 2010

J. Neurosci.

138

102

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Misexpression and cytosolic retention of peripheral myelin protein 22 (PMP22) within Schwann cells (SCs) is associated with a genetically heterogeneous group of demyelinating peripheral neuropathies. PMP22 overproducer C22 and spontaneous mutant Trembler J (TrJ) mice display neuropathic phenotypes and affected nerves contain abnormally localized PMP22. Nutrient deprivation-induced autophagy is able to suppress the formation of PMP22 aggregates in a toxin-induced cellular model, and improve locomotor performance and myelination in TrJ mice. As a step toward therapies, we assessed whether pharmacological activation of autophagy by rapamycin (RM) could facilitate the processing of PMP22 within neuropathic SCs and enhance their capacity to myelinate peripheral axons. Exposure of mouse SCs to RM induced autophagy in a dose- and time-dependent manner and decreased the accumulation of poly-ubiquitinated substrates. The treatment of myelinating dorsal root ganglion (DRG) explant cultures from neuropathic mice with RM (25 nM) improved the processing of PMP22 and increased the abundance and length of myelin internodes, as well as the expression of myelin proteins. Notably, RM is similarly effective in both the C22 and TrJ model, signifying that the benefit overlaps among distinct genetic models of PMP22 neuropathies. Furthermore, lentivirus-mediated shRNA knockdown of the autophagy-related gene 12 (Atg12) abolished the activation of autophagy and the increase in myelin proteins, demonstrating that autophagy is critical for the observed improvement. Together, these results support the potential use of RM and other autophagy-enhancing compounds as therapeutic agents for PMP22-associated demyelinating neuropathies.

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A molecular basis for hereditary motor and sensory neuropathy disorders

Cited by 11 publications

References 96 publications

Conduction Block in PMP22 Deficiency

Conduction Block in PMP22 Deficiency

The Gdap1 knockout mouse mechanistically links redox control to Charcot–Marie–Tooth disease

Rapamycin Activates Autophagy and Improves Myelination in Explant Cultures from Neuropathic Mice

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