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Research Article
Loss of the E3 ubiquitin ligase LRSAM1 sensitizes peripheral axons to degeneration in a mouse model of Charcot-Marie-Tooth disease
Laurent P. Bogdanik, James N. Sleigh, Cong Tian, Mark E. Samuels, Karen Bedard, Kevin L. Seburn, Robert W. Burgess
Disease Models & Mechanisms 2013 : dmm.010942 doi: 10.1242/dmm.010942 Published 10 April 2013
Laurent P. Bogdanik
The Jackson Laboratory, Bar Harbor, ME, 04609, USA;
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James N. Sleigh
University of Oxford, South Parks Road, Oxford, UK;
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Cong Tian
The Jackson Laboratory, Bar Harbor, ME, 04609, USA;
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Mark E. Samuels
University of Montreal, Montreal, Quebec, Canada;
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Karen Bedard
Dalhousie University, Halifax, Nova Scotia, Canada
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Kevin L. Seburn
The Jackson Laboratory, Bar Harbor, ME, 04609, USA;
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Robert W. Burgess
The Jackson Laboratory, Bar Harbor, ME, 04609, USA;
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Summary

Charcot-Marie-Tooth disease (CMT) is a clinically and genetically heterogeneous condition characterized by peripheral axon degeneration with subsequent motor and sensory deficits. Several CMT gene products function in endosomal sorting and trafficking to the lysosome, suggesting that defects in this cellular pathway may present a common pathogenic mechanism for these conditions. LRSAM1 is an E3 ubiquitin ligase that is implicated in this process, and mutations in LRSAM1 have recently been shown to cause CMT. We have generated mouse mutations in Lrsam1 to create an animal model of this form of CMT (CMT2P). Mouse Lrsam1 is abundantly expressed in the motor and sensory neurons of the peripheral nervous system. Both homozygous and heterozygous mice have largely normal neuromuscular performance and only a very mild neuropathy phenotype with age. However, Lrsam1 mutant mice are more sensitive to challenge with acrylamide, a neurotoxic agent that causes axon degeneration, indicating the axons in the mutant mice are indeed compromised. In transfected cells, LRSAM1 primarily localizes in a perinuclear compartment immediately beyond the Golgi and shows little colocalization with components of the endosome to lysosome trafficking pathway, suggesting that other cellular mechanisms also merit consideration.

  • Received September 25, 2012.
  • Accepted March 6, 2013.

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial Share Alike License (http://creativecommons.org/licenses/by-nc-sa/3.0), which permits unrestricted non-commercial use, distribution and reproduction in any medium provided that the original work is properly cited and all further distributions of the work or adaptation are subject to the same Creative Commons License terms.

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Loss of the E3 ubiquitin ligase LRSAM1 sensitizes peripheral axons to degeneration in a mouse model of Charcot-Marie-Tooth disease
Laurent P. Bogdanik, James N. Sleigh, Cong Tian, Mark E. Samuels, Karen Bedard, Kevin L. Seburn, Robert W. Burgess
Disease Models & Mechanisms 2013 : dmm.010942 doi: 10.1242/dmm.010942 Published 10 April 2013
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Loss of the E3 ubiquitin ligase LRSAM1 sensitizes peripheral axons to degeneration in a mouse model of Charcot-Marie-Tooth disease
Laurent P. Bogdanik, James N. Sleigh, Cong Tian, Mark E. Samuels, Karen Bedard, Kevin L. Seburn, Robert W. Burgess
Disease Models & Mechanisms 2013 : dmm.010942 doi: 10.1242/dmm.010942 Published 10 April 2013

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