Conduction Block in PMP22 Deficiency

Bai, Yunhong; Zhang, Xuebao; Katona, István; Saporta, Mario; Shy, Michael E.; O’Malley, Heather A.; Isom, Lori L.; Suter, Ueli; Li, Jun

doi:10.1523/jneurosci.4264-09.2010

Cited by 57 publications

(112 citation statements)

References 54 publications

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“…We also envisage that hampered biomechanical communication between neurites and the ECM is involved in pathogenesis of the inherited neurological disorders Charcot-Marie-Tooth 1A (CMT1A) and hereditary neuropathy with liability to pressure pulse (HNPP). CMT1A and HNPP are closely associated with biomechanical vulnerability entailing nerves which become prone to action potential conduction block and motoric disorders [16-18]. Growth cone-ECM interactions are important for force generation, axonal growth and guidance during nervous system development [2].…”

Section: Discussionmentioning

confidence: 99%

Mechanosensitivity of Embryonic Neurites Promotes Their Directional Extension and Schwann Cells Progenitors Migration

Rosso

Young²,

Shahin³

2017

Cell Physiol Biochem

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Background/Aims: Migration of Schwann cells (SCs) progenitors and neurite outgrowth from embryonic dorsal root ganglions (DRGs) are two central events during the development of the peripheral nervous system (PNS). How these two enthralling events preceding myelination are promoted is of great relevance from basic research and clinical aspects alike. Recent evidence demonstrates that biophysical cues (extracellular matrix stiffness) and biochemical signaling act in concert to regulate PNS myelination. Microenvironment stiffness of SCs progenitors and embryonic neurites dynamically changes during development. Methods: DRG explants were isolated from day 12.5 to 13.5 mice embryos and plated on laminin-coated substrates with varied stiffness values. After 4 days in culture and immunostaining with specific markers, neurite outgrowth pattern, SCs progenitors migration, and growth cone shape and advance were analyzed with confocal fluorescence microscopy. Results: We found out that growing substrate stiffness promotes directional neurite outgrowth, SCs progenitors migration, growth cone advance and presumably axons fasciculation. Conclusions: DRG explants are in vitro models for the research of PNS development, myelination and regeneration. Consequently, we conclude the following: Our observations point out the importance of mechanosensitivity for the PNS. At the same time, they prompt the investigation of the important yet unclear links between PNS biomechanics and inherited neuropathies with myelination disorders such as Charcot-Marie-Tooth 1A and hereditary neuropathy with liability to pressure palsies. Finally, they encourage the consideration of mechanosensitivity in bioengineering of scaffolds to aid nerve regeneration after injury.

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Section: Discussionmentioning

confidence: 99%

Mechanosensitivity of Embryonic Neurites Promotes Their Directional Extension and Schwann Cells Progenitors Migration

Rosso

Young²,

Shahin³

2017

Cell Physiol Biochem

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“…Demyelination of the AN is also reported in sensorineural deafness (42) and has been suggested to play a role in auditory neuropathy (50), a hearing disorder characterized by absent auditory brainstem responses with preserved outer hair cell function. Myelin disruption results in increased membrane time constants, decreased conduction velocity (51), and decreased membrane resistance (52,53), all of which could lead to conduction block (54). Conduction block could result in failure of transmitter release at the pathologically unmyelinated AN terminals, and this could explain why FC maximal firing could not be achieved even when stimulating at amplitudes allowing maximal AN fiber recruitment.…”

Section: Discussionmentioning

confidence: 99%

Mechanisms contributing to central excitability changes during hearing loss

Pilati¹,

Ison

Barker³

et al. 2012

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

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Exposure to loud sound causes cochlear damage resulting in hearing loss and tinnitus. Tinnitus has been related to hyperactivity in the central auditory pathway occurring weeks after loud sound exposure. However, central excitability changes concomitant to hearing loss and preceding those periods of hyperactivity, remain poorly explored. Here we investigate mechanisms contributing to excitability changes in the dorsal cochlear nucleus (DCN) shortly after exposure to loud sound that produces hearing loss. We show that acoustic overexposure alters synaptic transmission originating from the auditory and the multisensory pathway within the DCN in different ways. A reduction in the number of myelinated auditory nerve fibers leads to a reduced maximal firing rate of DCN principal cells, which cannot be restored by increasing auditory nerve fiber recruitment. In contrast, a decreased membrane resistance of DCN granule cells (multisensory inputs) leads to a reduced maximal firing rate of DCN principal cells that is overcome when additional multisensory fibers are recruited. Furthermore, gain modulation by inhibitory synaptic transmission is disabled in both auditory and multisensory pathways. These cellular mechanisms that contribute to decreased cellular excitability in the central auditory pathway are likely to represent early neurobiological markers of hearing loss and may suggest interventions to delay or stop the development of hyperactivity that has been associated with tinnitus.auditory brainstem | fusiform cell | parallel fiber | deafness | whole-cell patch I t is well established that exposure to loud sound causes damage to the cochlea and results in an elevation of hearing thresholds (1) often accompanied by a reduction of auditory nerve (AN) firing rate (2-4). Although peripheral cellular mechanisms contributing to hearing loss have been thoroughly described (5-11), mechanisms in the central auditory system involved in the early stages of hearing loss following acoustic overexposure (AOE) are poorly understood. The dorsal cochlear nucleus (DCN) is one of the first relays within the central auditory pathway (12). Hyperactivity in the DCN has been reported weeks after AOE in vivo and in brain slices and has been correlated with tinnitus (13-15). Our recent study showed the presence of bursts in DCN fusiform cells (FCs) just a few days after AOE (16). Therefore, the aim of the current study was to investigate synaptic transmission at this early time point after AOE and determine whether changes in auditory or multisensory (MS) inputs to FCs might contribute to the altered excitability in the DCN. We postulate that changes following AOE could represent the earliest modifications of the central auditory pathway preceding the later development of DCN hyperactivity and tinnitus. DCN FCs integrate the acoustic information from AN fibers with MS signals transmitted via granule cell axons (parallel fibers) (17-19). DCN granule cells and their parallel fiber axons represent a site of integration of multimodal sensory in...

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“…These results show that clinically unaffected nerves in the upper and lower limbs also displayed the generalized slowing of motor and sensory nerve conduction velocities and delayed distal motor latencies, consistent with the previous literatures [5,16] (table 1). The mechanism of slowing nerve conduction velocity might be involved in two aspects: (1) The lowered ratio of axon diameter to external diameter could rapidly raise axial resistance to action potential propagation [18,19]. Furthermore, when the nerve is compressed, the axons are even further stretching and thinning [19].…”

Section: Discussionmentioning

confidence: 99%

“…The mechanism of slowing nerve conduction velocity might be involved in two aspects: (1) The lowered ratio of axon diameter to external diameter could rapidly raise axial resistance to action potential propagation [18,19]. Furthermore, when the nerve is compressed, the axons are even further stretching and thinning [19]. (2) The multiple defects in the myelin sheath might indicate a pre-existing damage that produced increased leakage and slowing in conduction [18].…”

Section: Discussionmentioning

confidence: 99%

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Hereditary Neuropathy with Liability to Pressure Palsy: An Investigation in a Rare and Large Chinese Family

et al. 2012

Eur Neurol

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Background: Hereditary neuropathy with liability to pressure palsy (HNPP), mainly associated with the peripheral myelin protein 22 (PMP22) gene, is generally an autosomal-dominant inherited peripheral neuropathy. The present large family including four generations provides an exciting opportunity to gain important insights into HNPP in China. Patients and Methods: A large 43-member family with ten members suspected to be affected by HNPP was studied. Neurologic examinations, electrophysiological and neuropathological studies and molecular genetic testing were used for these kindred. Results: Clinically, the proband had limb hyposthenia and atrophy, and his mother showed declined tendon reflexes in the right lower limb. Electrophysiologically, sensory and motor nerve conduction velocities were generalized reduced. Sural nerve biopsy for the proband showed focal thickesning of the myelin sheaths. Furthermore, real-time quantitative PCR demonstrated that the PMP22 gene has a higher Ct value than reference gene in all suspected patients. Conclusions: These results indicated that the family is indeed a rare and large pedigree of HNPP caused by the deletion of PMP22 gene. Given that the suspected patient in the fourth generation is absent, this family is still worthy of further follow-up study.

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Conduction Block in PMP22 Deficiency

Cited by 57 publications

References 54 publications

Mechanosensitivity of Embryonic Neurites Promotes Their Directional Extension and Schwann Cells Progenitors Migration

Mechanosensitivity of Embryonic Neurites Promotes Their Directional Extension and Schwann Cells Progenitors Migration

Mechanisms contributing to central excitability changes during hearing loss

Hereditary Neuropathy with Liability to Pressure Palsy: An Investigation in a Rare and Large Chinese Family

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