Cargando…

Nmnat mitigates sensory dysfunction in a Drosophila model of paclitaxel-induced peripheral neuropathy

Chemotherapy-induced peripheral neuropathy (CIPN) is the major dose-limiting side effect of many commonly used chemotherapeutic agents, including paclitaxel. Currently, there are no neuroprotective or effective symptomatic treatments for CIPN. Lack of understanding of the in vivo mechanisms of CIPN...

Descripción completa

Detalles Bibliográficos
Autores principales: Brazill, Jennifer M., Cruz, Beverley, Zhu, Yi, Zhai, R. Grace
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Company of Biologists Ltd 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6031360/
https://www.ncbi.nlm.nih.gov/pubmed/29716954
http://dx.doi.org/10.1242/dmm.032938
_version_ 1783337301121695744
author Brazill, Jennifer M.
Cruz, Beverley
Zhu, Yi
Zhai, R. Grace
author_facet Brazill, Jennifer M.
Cruz, Beverley
Zhu, Yi
Zhai, R. Grace
author_sort Brazill, Jennifer M.
collection PubMed
description Chemotherapy-induced peripheral neuropathy (CIPN) is the major dose-limiting side effect of many commonly used chemotherapeutic agents, including paclitaxel. Currently, there are no neuroprotective or effective symptomatic treatments for CIPN. Lack of understanding of the in vivo mechanisms of CIPN has greatly impeded the identification of therapeutic targets. Here, we optimized a model of paclitaxel-induced peripheral neuropathy using Drosophila larvae that recapitulates aspects of chemotherapy-induced sensory dysfunction. We showed that nociceptive sensitivity is associated with disrupted organization of microtubule-associated MAP1B/Futsch and aberrant stabilization of peripheral sensory dendrites. These findings establish a robust and amenable model for studying peripheral mechanisms of CIPN. Using this model, we uncovered a critical role for nicotinamide mononucleotide adenylyltransferase (Nmnat) in maintaining the integrity and function of peripheral sensory neurons and uncovered Nmnat's therapeutic potential against diverse sensory symptoms of CIPN.
format Online
Article
Text
id pubmed-6031360
institution National Center for Biotechnology Information
language English
publishDate 2018
publisher The Company of Biologists Ltd
record_format MEDLINE/PubMed
spelling pubmed-60313602018-07-06 Nmnat mitigates sensory dysfunction in a Drosophila model of paclitaxel-induced peripheral neuropathy Brazill, Jennifer M. Cruz, Beverley Zhu, Yi Zhai, R. Grace Dis Model Mech Research Article Chemotherapy-induced peripheral neuropathy (CIPN) is the major dose-limiting side effect of many commonly used chemotherapeutic agents, including paclitaxel. Currently, there are no neuroprotective or effective symptomatic treatments for CIPN. Lack of understanding of the in vivo mechanisms of CIPN has greatly impeded the identification of therapeutic targets. Here, we optimized a model of paclitaxel-induced peripheral neuropathy using Drosophila larvae that recapitulates aspects of chemotherapy-induced sensory dysfunction. We showed that nociceptive sensitivity is associated with disrupted organization of microtubule-associated MAP1B/Futsch and aberrant stabilization of peripheral sensory dendrites. These findings establish a robust and amenable model for studying peripheral mechanisms of CIPN. Using this model, we uncovered a critical role for nicotinamide mononucleotide adenylyltransferase (Nmnat) in maintaining the integrity and function of peripheral sensory neurons and uncovered Nmnat's therapeutic potential against diverse sensory symptoms of CIPN. The Company of Biologists Ltd 2018-06-01 2018-06-12 /pmc/articles/PMC6031360/ /pubmed/29716954 http://dx.doi.org/10.1242/dmm.032938 Text en © 2018. Published by The Company of Biologists Ltd http://creativecommons.org/licenses/by/3.0This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.
spellingShingle Research Article
Brazill, Jennifer M.
Cruz, Beverley
Zhu, Yi
Zhai, R. Grace
Nmnat mitigates sensory dysfunction in a Drosophila model of paclitaxel-induced peripheral neuropathy
title Nmnat mitigates sensory dysfunction in a Drosophila model of paclitaxel-induced peripheral neuropathy
title_full Nmnat mitigates sensory dysfunction in a Drosophila model of paclitaxel-induced peripheral neuropathy
title_fullStr Nmnat mitigates sensory dysfunction in a Drosophila model of paclitaxel-induced peripheral neuropathy
title_full_unstemmed Nmnat mitigates sensory dysfunction in a Drosophila model of paclitaxel-induced peripheral neuropathy
title_short Nmnat mitigates sensory dysfunction in a Drosophila model of paclitaxel-induced peripheral neuropathy
title_sort nmnat mitigates sensory dysfunction in a drosophila model of paclitaxel-induced peripheral neuropathy
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6031360/
https://www.ncbi.nlm.nih.gov/pubmed/29716954
http://dx.doi.org/10.1242/dmm.032938
work_keys_str_mv AT brazilljenniferm nmnatmitigatessensorydysfunctioninadrosophilamodelofpaclitaxelinducedperipheralneuropathy
AT cruzbeverley nmnatmitigatessensorydysfunctioninadrosophilamodelofpaclitaxelinducedperipheralneuropathy
AT zhuyi nmnatmitigatessensorydysfunctioninadrosophilamodelofpaclitaxelinducedperipheralneuropathy
AT zhairgrace nmnatmitigatessensorydysfunctioninadrosophilamodelofpaclitaxelinducedperipheralneuropathy