Journal article
Myelin abnormality in Charcot-Marie-Tooth type 4J recapitulates features of acquired demyelination
Annals of neurology, Vol.83(4), pp.756-770
04/2018
DOI: 10.1002/ana.25198
PMCID: PMC5912982
PMID: 29518270
Abstract
Charcot-Marie-Tooth type 4J (CMT4J) is a rare autosomal recessive neuropathy caused by mutations in FIG4 that result in loss of FIG4 protein. This study investigates the natural history and mechanisms of segmental demyelination in CMT4J.\nOver the past 9 years, we have enrolled and studied a cohort of 12 CMT4J patients, including 6 novel FIG4 mutations. We evaluated these patients and related mouse models using morphological, electrophysiological, and biochemical approaches.\nWe found sensory motor demyelinating polyneuropathy consistently in all patients. This underlying myelin pathology was associated with nonuniform slowing of conduction velocities, conduction block, and temporal dispersion on nerve conduction studies, which resemble those features in acquired demyelinating peripheral nerve diseases. Segmental demyelination was also confirmed in mice without Fig4 (Fig4\n). The demyelination was associated with an increase of Schwann cell dedifferentiation and macrophages in spinal roots where nerve-blood barriers are weak. Schwann cell dedifferentiation was induced by the increasing intracellular Ca\n. Suppression of Ca\nlevel by a chelator reduced dedifferentiation and demyelination of Schwann cells in vitro and in vivo. Interestingly, cell-specific knockout of Fig4 in mouse Schwann cells or neurons failed to cause segmental demyelination.\nMyelin change in CMT4J recapitulates the features of acquired demyelinating neuropathies. This pathology is not Schwann cell autonomous. Instead, it relates to systemic processes involving interactions of multiple cell types and abnormally elevated intracellular Ca\n. Injection of a Ca\nchelator into Fig4\nmice improved segmental demyelination, thereby providing a therapeutic strategy against demyelination. Ann Neurol 2018;83:756-770.
Details
- Title: Subtitle
- Myelin abnormality in Charcot-Marie-Tooth type 4J recapitulates features of acquired demyelination
- Creators
- Bo Hu - Department of Neurology, Center for Human Genetic Research, and Vanderbilt Brain Institute, Vanderbilt University Medical Center, Nashville, TNMegan McCollum - Department of Neurology, Center for Human Genetic Research, and Vanderbilt Brain Institute, Vanderbilt University Medical Center, Nashville, TNVignesh Ravi - Department of Neurology, Center for Human Genetic Research, and Vanderbilt Brain Institute, Vanderbilt University Medical Center, Nashville, TNSezgi Arpag - Department of Neurology, Center for Human Genetic Research, and Vanderbilt Brain Institute, Vanderbilt University Medical Center, Nashville, TNDaniel Moiseev - Department of Neurology, Center for Human Genetic Research, and Vanderbilt Brain Institute, Vanderbilt University Medical Center, Nashville, TNRyan Castoro - Department of Physical Medicine and Rehabilitation, Vanderbilt University Medical Center, Nashville, TNBret Mobley - Department of Pathology, Vanderbilt University Medical Center, Nashville, TNBryan Burnette - Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TNCarly Siskind - Department of Neurology, Stanford University, Palo Alto, CAJohn Day - Department of Neurology, Stanford University, Palo Alto, CARobin Yawn - Department of Neurology, Center for Human Genetic Research, and Vanderbilt Brain Institute, Vanderbilt University Medical Center, Nashville, TNShawna Feely - Department of Neurology, University of Iowa, Iowa City, IAYuebing Li - Department of Neurology, Cleveland Clinic Foundation, Cleveland, OHQing Yan - Department of Laboratory Medicine, Second Affiliated Hospital of Qingdao University, Qingdao, ChinaMichael Shy - Department of Neurology, University of Iowa, Iowa City, IAJun Li - Tennessee Valley Healthcare System-Nashville VA, Nashville, TN
- Resource Type
- Journal article
- Publication Details
- Annals of neurology, Vol.83(4), pp.756-770
- Publisher
- United States
- DOI
- 10.1002/ana.25198
- PMID
- 29518270
- PMCID
- PMC5912982
- ISSN
- 0364-5134
- eISSN
- 1531-8249
- Grant note
- UL1 TR000445 / NCATS NIH HHS\nR01 NS066927 / NINDS NIH HHS\nU54 NS065712 / NINDS NIH HHS
- Language
- English
- Date published
- 04/2018
- Academic Unit
- Neurology; Molecular Physiology and Biophysics; Anatomy and Cell Biology; Stead Family Department of Pediatrics; Iowa Neuroscience Institute
- Record Identifier
- 9984070948702771
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