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Loss of Fig4 in both Schwann cells and motor neurons contributes to CMT4J neuropathy
Mutations of FIG4 are responsible for Yunis-Varón syndrome, familial epilepsy with polymicrogyria, and Charcot-Marie-Tooth type 4J neuropathy (CMT4J). Although loss of the FIG4 phospholipid phosphatase consistently causes decreased PtdIns(3,5)P(2) levels, cell-specific sensitivity to partial loss of...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4275070/ https://www.ncbi.nlm.nih.gov/pubmed/25187576 http://dx.doi.org/10.1093/hmg/ddu451 |
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author | Vaccari, Ilaria Carbone, Antonietta Previtali, Stefano Carlo Mironova, Yevgeniya A. Alberizzi, Valeria Noseda, Roberta Rivellini, Cristina Bianchi, Francesca Del Carro, Ubaldo D'Antonio, Maurizio Lenk, Guy M. Wrabetz, Lawrence Giger, Roman J. Meisler, Miriam H. Bolino, Alessandra |
author_facet | Vaccari, Ilaria Carbone, Antonietta Previtali, Stefano Carlo Mironova, Yevgeniya A. Alberizzi, Valeria Noseda, Roberta Rivellini, Cristina Bianchi, Francesca Del Carro, Ubaldo D'Antonio, Maurizio Lenk, Guy M. Wrabetz, Lawrence Giger, Roman J. Meisler, Miriam H. Bolino, Alessandra |
author_sort | Vaccari, Ilaria |
collection | PubMed |
description | Mutations of FIG4 are responsible for Yunis-Varón syndrome, familial epilepsy with polymicrogyria, and Charcot-Marie-Tooth type 4J neuropathy (CMT4J). Although loss of the FIG4 phospholipid phosphatase consistently causes decreased PtdIns(3,5)P(2) levels, cell-specific sensitivity to partial loss of FIG4 function may differentiate FIG4-associated disorders. CMT4J is an autosomal recessive neuropathy characterized by severe demyelination and axonal loss in human, with both motor and sensory involvement. However, it is unclear whether FIG4 has cell autonomous roles in both motor neurons and Schwann cells, and how loss of FIG4/PtdIns(3,5)P(2)-mediated functions contribute to the pathogenesis of CMT4J. Here, we report that mice with conditional inactivation of Fig4 in motor neurons display neuronal and axonal degeneration. In contrast, conditional inactivation of Fig4 in Schwann cells causes demyelination and defects in autophagy-mediated degradation. Moreover, Fig4-regulated endolysosomal trafficking in Schwann cells is essential for myelin biogenesis during development and for proper regeneration/remyelination after injury. Our data suggest that impaired endolysosomal trafficking in both motor neurons and Schwann cells contributes to CMT4J neuropathy. |
format | Online Article Text |
id | pubmed-4275070 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-42750702015-01-28 Loss of Fig4 in both Schwann cells and motor neurons contributes to CMT4J neuropathy Vaccari, Ilaria Carbone, Antonietta Previtali, Stefano Carlo Mironova, Yevgeniya A. Alberizzi, Valeria Noseda, Roberta Rivellini, Cristina Bianchi, Francesca Del Carro, Ubaldo D'Antonio, Maurizio Lenk, Guy M. Wrabetz, Lawrence Giger, Roman J. Meisler, Miriam H. Bolino, Alessandra Hum Mol Genet Articles Mutations of FIG4 are responsible for Yunis-Varón syndrome, familial epilepsy with polymicrogyria, and Charcot-Marie-Tooth type 4J neuropathy (CMT4J). Although loss of the FIG4 phospholipid phosphatase consistently causes decreased PtdIns(3,5)P(2) levels, cell-specific sensitivity to partial loss of FIG4 function may differentiate FIG4-associated disorders. CMT4J is an autosomal recessive neuropathy characterized by severe demyelination and axonal loss in human, with both motor and sensory involvement. However, it is unclear whether FIG4 has cell autonomous roles in both motor neurons and Schwann cells, and how loss of FIG4/PtdIns(3,5)P(2)-mediated functions contribute to the pathogenesis of CMT4J. Here, we report that mice with conditional inactivation of Fig4 in motor neurons display neuronal and axonal degeneration. In contrast, conditional inactivation of Fig4 in Schwann cells causes demyelination and defects in autophagy-mediated degradation. Moreover, Fig4-regulated endolysosomal trafficking in Schwann cells is essential for myelin biogenesis during development and for proper regeneration/remyelination after injury. Our data suggest that impaired endolysosomal trafficking in both motor neurons and Schwann cells contributes to CMT4J neuropathy. Oxford University Press 2015-01-15 2014-09-03 /pmc/articles/PMC4275070/ /pubmed/25187576 http://dx.doi.org/10.1093/hmg/ddu451 Text en © The Author 2014. Published by Oxford University Press. http://creativecommons.org/licenses/by/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Articles Vaccari, Ilaria Carbone, Antonietta Previtali, Stefano Carlo Mironova, Yevgeniya A. Alberizzi, Valeria Noseda, Roberta Rivellini, Cristina Bianchi, Francesca Del Carro, Ubaldo D'Antonio, Maurizio Lenk, Guy M. Wrabetz, Lawrence Giger, Roman J. Meisler, Miriam H. Bolino, Alessandra Loss of Fig4 in both Schwann cells and motor neurons contributes to CMT4J neuropathy |
title | Loss of Fig4 in both Schwann cells and motor neurons contributes to CMT4J neuropathy |
title_full | Loss of Fig4 in both Schwann cells and motor neurons contributes to CMT4J neuropathy |
title_fullStr | Loss of Fig4 in both Schwann cells and motor neurons contributes to CMT4J neuropathy |
title_full_unstemmed | Loss of Fig4 in both Schwann cells and motor neurons contributes to CMT4J neuropathy |
title_short | Loss of Fig4 in both Schwann cells and motor neurons contributes to CMT4J neuropathy |
title_sort | loss of fig4 in both schwann cells and motor neurons contributes to cmt4j neuropathy |
topic | Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4275070/ https://www.ncbi.nlm.nih.gov/pubmed/25187576 http://dx.doi.org/10.1093/hmg/ddu451 |
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