Rippling is not always electrically silent in rippling muscle disease

Maki, Takakuni; Matsumoto, Riki; Kohara, Nobuo; Kondo, Takayuki; Son, Insuk; Mezaki, Takahiro; Nishino, Ichizo; Ikeda, Akio; Takahashi, Ryōsuke

doi:10.1002/mus.21947

Cited by 17 publications

(15 citation statements)

References 21 publications

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“…In the same model system, however, PMP22 was not retained in the ER, suggesting an independent mechanism for the transport of PMP22 and P0. PMP22 contains an evolutionary conserved CRAC motif in its fourth transmembrane domain (Gould et al, 2005;Sedzik et al, 2013) and mutations in this region have been linked to severe neuropathies (Ionasescu et al, 1997;Ikegami et al, 1998;Parman et al, 1999;Ohnishi et al, 2000;Maki et al, 2011). Therefore, given the intracellular retention of cholesterol in the absence of PMP22 shown here, it is plausible that, similar to PLP, PMP22 is key for the cholesterol trafficking from trans-Golgi to the plasma membrane.…”

Section: Discussionmentioning

confidence: 82%

PMP22 Regulates Cholesterol Trafficking and ABCA1-Mediated Cholesterol Efflux

Zhou¹,

Miles

Tavori

et al. 2019

J. Neurosci.

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The absence of functional peripheral myelin protein 22 (PMP22) is associated with shortened lifespan in rodents and severe peripheral nerve myelin abnormalities in several species including humans. Schwann cells and nerves from PMP22 knock-out (KO) mice show deranged cholesterol distribution and aberrant lipid raft morphology, supporting an unrecognized role for PMP22 in cellular lipid metabolism. To examine the mechanisms underlying these abnormalities, we studied Schwann cells and nerves from male and female PMP22 KO mice. Whole-cell current-clamp recordings in cultured Schwann cells revealed increased membrane capacitance and decreased membrane resistance in the absence of PMP22, which was consistent with a reduction in membrane cholesterol. Nerves from PMP22-deficient mice contained abnormal lipid droplets, with both mRNA and protein levels of apolipoprotein E (apoE) and ATPbinding cassette transporter A1 (ABCA1) being highly upregulated. Despite the upregulation of ABCA1 and apoE, the absence of PMP22 resulted in reduced localization of the transporter to the cell membrane and diminished secretion of apoE. The absence of PMP22 also impaired ABCA1-mediated cholesterol efflux capacity. In nerves from ABCA1 KO mice, the expression of PMP22 was significantly elevated and the subcellular processing of the overproduced protein was aberrant. In wild-type samples, double immunolabeling identified overlapping distribution of PMP22 and ABCA1 at the Schwann cell plasma membrane and the two proteins were coimmunoprecipitated from Schwann cell and nerve lysates. Together, these results reveal a novel role for PMP22 in regulating lipid metabolism and cholesterol trafficking through functional interaction with the cholesterol efflux regulatory protein ABCA1. Significance StatementUnderstanding the subcellular events that underlie abnormal myelin formation in hereditary neuropathies is critical for advancing therapy development. Peripheral myelin protein 22 (PMP22) is an essential peripheral myelin protein because its genetic abnormalities account for ϳ80% of hereditary neuropathies. Here, we demonstrate that in the absence of PMP22, the cellular and electrophysiological properties of the Schwann cells' plasma membrane are altered and cholesterol trafficking and lipid homeostasis are perturbed. The molecular mechanisms for these abnormalities involve a functional interplay among PMP22, cholesterol, apolipoprotein E, and the major cholesterol-efflux transporter protein ATP-binding cassette transporter A1 (ABCA1). These findings establish a critical role for PMP22 in the maintenance of cholesterol homeostasis in Schwann cells.

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Section: Discussionmentioning

confidence: 82%

PMP22 Regulates Cholesterol Trafficking and ABCA1-Mediated Cholesterol Efflux

Zhou¹,

Miles

Tavori

et al. 2019

J. Neurosci.

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“…Rippling muscle disease (RMD) is a muscle hyperexcitability disorder, clinically characterized by painful muscle stiffness, rippling of the muscle, and percussion‐induced muscle mounding or rapid contraction. Muscle rippling is generally electrically silent, but associated electrical activity has been occasionally reported . RMD can be hereditary, as result of mutations in the caveolin‐3– or cavin‐1–encoding gene, or acquired, due to an immune‐mediated process .…”

Section: Lgmd Subgroupsmentioning

confidence: 99%

“…Muscle rippling is generally electrically silent, but associated electrical activity has been occasionally reported. 87,88 RMD can be hereditary, as result of mutations in the caveolin-3or cavin-1-encoding gene, or acquired, due to an immune-mediated process. 87,89 The mosaic pattern of sarcolemmal caveolin-3 deficiency, detected by immunocytochemical study, distinguishes the immune-mediated RMD from the hereditary RMD, which is characterized by a more homogeneous loss of caveolin-3 immunoreactivity.…”

Section: Figurementioning

confidence: 99%

Untangling the complexity of limb‐girdle muscular dystrophies

Liewluck

Milone

2018

Muscle and Nerve

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The limb-girdle muscular dystrophies (LGMDs) are a group of genetically heterogeneous, autosomal inherited muscular dystrophies with a childhood to adult onset, manifesting with hip- and shoulder-girdle muscle weakness. When the term LGMD was first conceptualized in 1954, it was thought to be a single entity. Currently, there are 8 autosomal dominant (LGMD1A-1H) and 26 autosomal recessive (LGMD2A-2Z) variants according to the Online Mendelian Inheritance in Man database. In addition, there are other genetically identified muscular dystrophies with an LGMD phenotype not yet classified as LGMD. This highlights the entanglement of LGMDs, which represents an area in continuous expansion. Herein we aim to simplify the complexity of LGMDs by subgrouping them on the basis of the underlying defective protein and impaired function. Muscle Nerve 58: 167-177, 2018.

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“…Thus, the sustained motor activity originates directly from muscle. The routine EMG is normal, but percussion elicits irregular and decrementing bursts of activity …”

Section: Differential Diagnosismentioning

confidence: 99%

Isaacs syndrome: A review

2015

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Isaacs syndrome is a peripheral nerve hyperexcitability (PNH) syndrome that presents as continuous motor activity. Clinical findings include cramps, fasciculations, and myokymia. Electrodiagnosis plays a key role in diagnosis by demonstrating after-discharges on nerve conduction studies, and fasciculation potentials, myokymic discharges, neuromyotonic discharges, and other types of abnormal spontaneous activity on needle examination. Etiopathogenesis involves the interaction of genetic, autoimmune, and paraneoplastic factors, which requires a broad-ranging evaluation for underlying causes. Initial treatment is symptomatic, but immune therapy is often needed and can be effective. The purpose of this review is to describe the syndrome and its pathogenesis, assist the reader in evaluating patients with suspected Isaacs syndrome and distinguishing it from other disorders of PNH, and suggest an approach to management, including both symptomatic and immunomodulating therapy.

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Rippling is not always electrically silent in rippling muscle disease

Cited by 17 publications

References 21 publications

PMP22 Regulates Cholesterol Trafficking and ABCA1-Mediated Cholesterol Efflux

PMP22 Regulates Cholesterol Trafficking and ABCA1-Mediated Cholesterol Efflux

Untangling the complexity of limb‐girdle muscular dystrophies

Isaacs syndrome: A review

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