Cargando…

Endoplasmic reticulum stress in spinal and bulbar muscular atrophy: a potential target for therapy

Spinal and bulbar muscular atrophy is an X-linked degenerative motor neuron disease caused by an abnormal expansion in the polyglutamine encoding CAG repeat of the androgen receptor gene. There is evidence implicating endoplasmic reticulum stress in the development and progression of neurodegenerati...

Descripción completa

Detalles Bibliográficos
Autores principales: Montague, Karli, Malik, Bilal, Gray, Anna L., La Spada, Albert R., Hanna, Michael G., Szabadkai, Gyorgy, Greensmith, Linda
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4065020/
https://www.ncbi.nlm.nih.gov/pubmed/24898351
http://dx.doi.org/10.1093/brain/awu114
_version_ 1782322014254530560
author Montague, Karli
Malik, Bilal
Gray, Anna L.
La Spada, Albert R.
Hanna, Michael G.
Szabadkai, Gyorgy
Greensmith, Linda
author_facet Montague, Karli
Malik, Bilal
Gray, Anna L.
La Spada, Albert R.
Hanna, Michael G.
Szabadkai, Gyorgy
Greensmith, Linda
author_sort Montague, Karli
collection PubMed
description Spinal and bulbar muscular atrophy is an X-linked degenerative motor neuron disease caused by an abnormal expansion in the polyglutamine encoding CAG repeat of the androgen receptor gene. There is evidence implicating endoplasmic reticulum stress in the development and progression of neurodegenerative disease, including polyglutamine disorders such as Huntington’s disease and in motor neuron disease, where cellular stress disrupts functioning of the endoplasmic reticulum, leading to induction of the unfolded protein response. We examined whether endoplasmic reticulum stress is also involved in the pathogenesis of spinal and bulbar muscular atrophy. Spinal and bulbar muscular atrophy mice that carry 100 pathogenic polyglutamine repeats in the androgen receptor, and develop a late-onset neuromuscular phenotype with motor neuron degeneration, were studied. We observed a disturbance in endoplasmic reticulum-associated calcium homeostasis in cultured embryonic motor neurons from spinal and bulbar muscular atrophy mice, which was accompanied by increased endoplasmic reticulum stress. Furthermore, pharmacological inhibition of endoplasmic reticulum stress reduced the endoplasmic reticulum-associated cell death pathway. Examination of spinal cord motor neurons of pathogenic mice at different disease stages revealed elevated expression of markers for endoplasmic reticulum stress, confirming an increase in this stress response in vivo. Importantly, the most significant increase was detected presymptomatically, suggesting that endoplasmic reticulum stress may play an early and possibly causal role in disease pathogenesis. Our results therefore indicate that the endoplasmic reticulum stress pathway could potentially be a therapeutic target for spinal and bulbar muscular atrophy and related polyglutamine diseases.
format Online
Article
Text
id pubmed-4065020
institution National Center for Biotechnology Information
language English
publishDate 2014
publisher Oxford University Press
record_format MEDLINE/PubMed
spelling pubmed-40650202014-06-23 Endoplasmic reticulum stress in spinal and bulbar muscular atrophy: a potential target for therapy Montague, Karli Malik, Bilal Gray, Anna L. La Spada, Albert R. Hanna, Michael G. Szabadkai, Gyorgy Greensmith, Linda Brain Original Articles Spinal and bulbar muscular atrophy is an X-linked degenerative motor neuron disease caused by an abnormal expansion in the polyglutamine encoding CAG repeat of the androgen receptor gene. There is evidence implicating endoplasmic reticulum stress in the development and progression of neurodegenerative disease, including polyglutamine disorders such as Huntington’s disease and in motor neuron disease, where cellular stress disrupts functioning of the endoplasmic reticulum, leading to induction of the unfolded protein response. We examined whether endoplasmic reticulum stress is also involved in the pathogenesis of spinal and bulbar muscular atrophy. Spinal and bulbar muscular atrophy mice that carry 100 pathogenic polyglutamine repeats in the androgen receptor, and develop a late-onset neuromuscular phenotype with motor neuron degeneration, were studied. We observed a disturbance in endoplasmic reticulum-associated calcium homeostasis in cultured embryonic motor neurons from spinal and bulbar muscular atrophy mice, which was accompanied by increased endoplasmic reticulum stress. Furthermore, pharmacological inhibition of endoplasmic reticulum stress reduced the endoplasmic reticulum-associated cell death pathway. Examination of spinal cord motor neurons of pathogenic mice at different disease stages revealed elevated expression of markers for endoplasmic reticulum stress, confirming an increase in this stress response in vivo. Importantly, the most significant increase was detected presymptomatically, suggesting that endoplasmic reticulum stress may play an early and possibly causal role in disease pathogenesis. Our results therefore indicate that the endoplasmic reticulum stress pathway could potentially be a therapeutic target for spinal and bulbar muscular atrophy and related polyglutamine diseases. Oxford University Press 2014-07 2014-06-04 /pmc/articles/PMC4065020/ /pubmed/24898351 http://dx.doi.org/10.1093/brain/awu114 Text en © The Author (2014). Published by Oxford University Press on behalf of the Guarantors of Brain. http://creativecommons.org/licenses/by/3.0/ This 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 reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Original Articles
Montague, Karli
Malik, Bilal
Gray, Anna L.
La Spada, Albert R.
Hanna, Michael G.
Szabadkai, Gyorgy
Greensmith, Linda
Endoplasmic reticulum stress in spinal and bulbar muscular atrophy: a potential target for therapy
title Endoplasmic reticulum stress in spinal and bulbar muscular atrophy: a potential target for therapy
title_full Endoplasmic reticulum stress in spinal and bulbar muscular atrophy: a potential target for therapy
title_fullStr Endoplasmic reticulum stress in spinal and bulbar muscular atrophy: a potential target for therapy
title_full_unstemmed Endoplasmic reticulum stress in spinal and bulbar muscular atrophy: a potential target for therapy
title_short Endoplasmic reticulum stress in spinal and bulbar muscular atrophy: a potential target for therapy
title_sort endoplasmic reticulum stress in spinal and bulbar muscular atrophy: a potential target for therapy
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4065020/
https://www.ncbi.nlm.nih.gov/pubmed/24898351
http://dx.doi.org/10.1093/brain/awu114
work_keys_str_mv AT montaguekarli endoplasmicreticulumstressinspinalandbulbarmuscularatrophyapotentialtargetfortherapy
AT malikbilal endoplasmicreticulumstressinspinalandbulbarmuscularatrophyapotentialtargetfortherapy
AT grayannal endoplasmicreticulumstressinspinalandbulbarmuscularatrophyapotentialtargetfortherapy
AT laspadaalbertr endoplasmicreticulumstressinspinalandbulbarmuscularatrophyapotentialtargetfortherapy
AT hannamichaelg endoplasmicreticulumstressinspinalandbulbarmuscularatrophyapotentialtargetfortherapy
AT szabadkaigyorgy endoplasmicreticulumstressinspinalandbulbarmuscularatrophyapotentialtargetfortherapy
AT greensmithlinda endoplasmicreticulumstressinspinalandbulbarmuscularatrophyapotentialtargetfortherapy