Cargando…

Histopathological Defects in Intestine in Severe Spinal Muscular Atrophy Mice Are Improved by Systemic Antisense Oligonucleotide Treatment

Gastrointestinal (GI) defects, including gastroesophageal reflux, constipation and delayed gastric emptying, are common in patients with spinal muscular atrophy (SMA). Similar GI dysmotility has been identified in mouse models with survival of motor neuron (SMN) protein deficiency. We previously des...

Descripción completa

Detalles Bibliográficos
Autores principales: Sintusek, Palittiya, Catapano, Francesco, Angkathunkayul, Napat, Marrosu, Elena, Parson, Simon H., Morgan, Jennifer E., Muntoni, Francesco, Zhou, Haiyan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4862622/
https://www.ncbi.nlm.nih.gov/pubmed/27163330
http://dx.doi.org/10.1371/journal.pone.0155032
_version_ 1782431368413708288
author Sintusek, Palittiya
Catapano, Francesco
Angkathunkayul, Napat
Marrosu, Elena
Parson, Simon H.
Morgan, Jennifer E.
Muntoni, Francesco
Zhou, Haiyan
author_facet Sintusek, Palittiya
Catapano, Francesco
Angkathunkayul, Napat
Marrosu, Elena
Parson, Simon H.
Morgan, Jennifer E.
Muntoni, Francesco
Zhou, Haiyan
author_sort Sintusek, Palittiya
collection PubMed
description Gastrointestinal (GI) defects, including gastroesophageal reflux, constipation and delayed gastric emptying, are common in patients with spinal muscular atrophy (SMA). Similar GI dysmotility has been identified in mouse models with survival of motor neuron (SMN) protein deficiency. We previously described vascular defects in skeletal muscle and spinal cord of SMA mice and we hypothesized that similar defects could be involved in the GI pathology observed in these mice. We therefore investigated the gross anatomical structure, enteric vasculature and neurons in the small intestine in a severe mouse model of SMA. We also assessed the therapeutic response of GI histopathology to systemic administration of morpholino antisense oligonucleotide (AON) designed to increase SMN protein expression. Significant anatomical and histopathological abnormalities, with striking reduction of vascular density, overabundance of enteric neurons and increased macrophage infiltration, were detected in the small intestine in SMA mice. After systemic AON treatment in neonatal mice, all the abnormalities observed were significantly restored to near-normal levels. We conclude that the observed GI histopathological phenotypes and functional defects observed in these SMA mice are strongly linked to SMN deficiency which can be rescued by systemic administration of AON. This study on the histopathological changes in the gastrointestinal system in severe SMA mice provides further indication of the complex role that SMN plays in multiple tissues and suggests that at least in SMA mice restoration of SMN production in peripheral tissues is essential for optimal outcome.
format Online
Article
Text
id pubmed-4862622
institution National Center for Biotechnology Information
language English
publishDate 2016
publisher Public Library of Science
record_format MEDLINE/PubMed
spelling pubmed-48626222016-05-18 Histopathological Defects in Intestine in Severe Spinal Muscular Atrophy Mice Are Improved by Systemic Antisense Oligonucleotide Treatment Sintusek, Palittiya Catapano, Francesco Angkathunkayul, Napat Marrosu, Elena Parson, Simon H. Morgan, Jennifer E. Muntoni, Francesco Zhou, Haiyan PLoS One Research Article Gastrointestinal (GI) defects, including gastroesophageal reflux, constipation and delayed gastric emptying, are common in patients with spinal muscular atrophy (SMA). Similar GI dysmotility has been identified in mouse models with survival of motor neuron (SMN) protein deficiency. We previously described vascular defects in skeletal muscle and spinal cord of SMA mice and we hypothesized that similar defects could be involved in the GI pathology observed in these mice. We therefore investigated the gross anatomical structure, enteric vasculature and neurons in the small intestine in a severe mouse model of SMA. We also assessed the therapeutic response of GI histopathology to systemic administration of morpholino antisense oligonucleotide (AON) designed to increase SMN protein expression. Significant anatomical and histopathological abnormalities, with striking reduction of vascular density, overabundance of enteric neurons and increased macrophage infiltration, were detected in the small intestine in SMA mice. After systemic AON treatment in neonatal mice, all the abnormalities observed were significantly restored to near-normal levels. We conclude that the observed GI histopathological phenotypes and functional defects observed in these SMA mice are strongly linked to SMN deficiency which can be rescued by systemic administration of AON. This study on the histopathological changes in the gastrointestinal system in severe SMA mice provides further indication of the complex role that SMN plays in multiple tissues and suggests that at least in SMA mice restoration of SMN production in peripheral tissues is essential for optimal outcome. Public Library of Science 2016-05-10 /pmc/articles/PMC4862622/ /pubmed/27163330 http://dx.doi.org/10.1371/journal.pone.0155032 Text en © 2016 Sintusek et al 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 use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Sintusek, Palittiya
Catapano, Francesco
Angkathunkayul, Napat
Marrosu, Elena
Parson, Simon H.
Morgan, Jennifer E.
Muntoni, Francesco
Zhou, Haiyan
Histopathological Defects in Intestine in Severe Spinal Muscular Atrophy Mice Are Improved by Systemic Antisense Oligonucleotide Treatment
title Histopathological Defects in Intestine in Severe Spinal Muscular Atrophy Mice Are Improved by Systemic Antisense Oligonucleotide Treatment
title_full Histopathological Defects in Intestine in Severe Spinal Muscular Atrophy Mice Are Improved by Systemic Antisense Oligonucleotide Treatment
title_fullStr Histopathological Defects in Intestine in Severe Spinal Muscular Atrophy Mice Are Improved by Systemic Antisense Oligonucleotide Treatment
title_full_unstemmed Histopathological Defects in Intestine in Severe Spinal Muscular Atrophy Mice Are Improved by Systemic Antisense Oligonucleotide Treatment
title_short Histopathological Defects in Intestine in Severe Spinal Muscular Atrophy Mice Are Improved by Systemic Antisense Oligonucleotide Treatment
title_sort histopathological defects in intestine in severe spinal muscular atrophy mice are improved by systemic antisense oligonucleotide treatment
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4862622/
https://www.ncbi.nlm.nih.gov/pubmed/27163330
http://dx.doi.org/10.1371/journal.pone.0155032
work_keys_str_mv AT sintusekpalittiya histopathologicaldefectsinintestineinseverespinalmuscularatrophymiceareimprovedbysystemicantisenseoligonucleotidetreatment
AT catapanofrancesco histopathologicaldefectsinintestineinseverespinalmuscularatrophymiceareimprovedbysystemicantisenseoligonucleotidetreatment
AT angkathunkayulnapat histopathologicaldefectsinintestineinseverespinalmuscularatrophymiceareimprovedbysystemicantisenseoligonucleotidetreatment
AT marrosuelena histopathologicaldefectsinintestineinseverespinalmuscularatrophymiceareimprovedbysystemicantisenseoligonucleotidetreatment
AT parsonsimonh histopathologicaldefectsinintestineinseverespinalmuscularatrophymiceareimprovedbysystemicantisenseoligonucleotidetreatment
AT morganjennifere histopathologicaldefectsinintestineinseverespinalmuscularatrophymiceareimprovedbysystemicantisenseoligonucleotidetreatment
AT muntonifrancesco histopathologicaldefectsinintestineinseverespinalmuscularatrophymiceareimprovedbysystemicantisenseoligonucleotidetreatment
AT zhouhaiyan histopathologicaldefectsinintestineinseverespinalmuscularatrophymiceareimprovedbysystemicantisenseoligonucleotidetreatment