Cargando…
Survival motor neuron protein and neurite degeneration are regulated by Gemin3 in spinal muscular atrophy motoneurons
Spinal Muscular Atrophy (SMA) is a genetic neuromuscular disorder caused by reduction of the ubiquitously expressed protein Survival Motor Neuron (SMN). Low levels of SMN impact on spinal cord motoneurons (MNs) causing their degeneration and progressive muscle weakness and atrophy. To study the mole...
Autores principales: | , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2022
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9813745/ https://www.ncbi.nlm.nih.gov/pubmed/36619669 http://dx.doi.org/10.3389/fncel.2022.1054270 |
_version_ | 1784863986728042496 |
---|---|
author | Miralles, Maria P. Sansa, Alba Beltran, Maria Soler, Rosa M. Garcera, Ana |
author_facet | Miralles, Maria P. Sansa, Alba Beltran, Maria Soler, Rosa M. Garcera, Ana |
author_sort | Miralles, Maria P. |
collection | PubMed |
description | Spinal Muscular Atrophy (SMA) is a genetic neuromuscular disorder caused by reduction of the ubiquitously expressed protein Survival Motor Neuron (SMN). Low levels of SMN impact on spinal cord motoneurons (MNs) causing their degeneration and progressive muscle weakness and atrophy. To study the molecular mechanisms leading to cell loss in SMN-reduced MNs, we analyzed the NF-κB intracellular pathway in SMA models. NF-κB pathway activation is required for survival and regulates SMN levels in cultured MNs. Here we describe that NF-κB members, inhibitor of kappa B kinase beta (IKKβ), and RelA, were reduced in SMA mouse and human MNs. In addition, we observed that Gemin3 protein level was decreased in SMA MNs, but not in non-neuronal SMA cells. Gemin3 is a core member of the SMN complex responsible for small nuclear ribonucleoprotein biogenesis, and it regulates NF-κB activation through the mitogen-activated protein kinase TAK1. Our experiments showed that Gemin3 knockdown reduced SMN, IKKβ, and RelA protein levels, and caused significant neurite degeneration. Overexpression of SMN increased Gemin3 protein in SMA MNs, but did not prevent neurite degeneration in Gemin3 knockdown cells. These data indicated that Gemin3 reduction may contribute to cell degeneration in SMA MNs. |
format | Online Article Text |
id | pubmed-9813745 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-98137452023-01-06 Survival motor neuron protein and neurite degeneration are regulated by Gemin3 in spinal muscular atrophy motoneurons Miralles, Maria P. Sansa, Alba Beltran, Maria Soler, Rosa M. Garcera, Ana Front Cell Neurosci Cellular Neuroscience Spinal Muscular Atrophy (SMA) is a genetic neuromuscular disorder caused by reduction of the ubiquitously expressed protein Survival Motor Neuron (SMN). Low levels of SMN impact on spinal cord motoneurons (MNs) causing their degeneration and progressive muscle weakness and atrophy. To study the molecular mechanisms leading to cell loss in SMN-reduced MNs, we analyzed the NF-κB intracellular pathway in SMA models. NF-κB pathway activation is required for survival and regulates SMN levels in cultured MNs. Here we describe that NF-κB members, inhibitor of kappa B kinase beta (IKKβ), and RelA, were reduced in SMA mouse and human MNs. In addition, we observed that Gemin3 protein level was decreased in SMA MNs, but not in non-neuronal SMA cells. Gemin3 is a core member of the SMN complex responsible for small nuclear ribonucleoprotein biogenesis, and it regulates NF-κB activation through the mitogen-activated protein kinase TAK1. Our experiments showed that Gemin3 knockdown reduced SMN, IKKβ, and RelA protein levels, and caused significant neurite degeneration. Overexpression of SMN increased Gemin3 protein in SMA MNs, but did not prevent neurite degeneration in Gemin3 knockdown cells. These data indicated that Gemin3 reduction may contribute to cell degeneration in SMA MNs. Frontiers Media S.A. 2022-12-22 /pmc/articles/PMC9813745/ /pubmed/36619669 http://dx.doi.org/10.3389/fncel.2022.1054270 Text en Copyright © 2022 Miralles, Sansa, Beltran, Soler and Garcera. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Cellular Neuroscience Miralles, Maria P. Sansa, Alba Beltran, Maria Soler, Rosa M. Garcera, Ana Survival motor neuron protein and neurite degeneration are regulated by Gemin3 in spinal muscular atrophy motoneurons |
title | Survival motor neuron protein and neurite degeneration are regulated by Gemin3 in spinal muscular atrophy motoneurons |
title_full | Survival motor neuron protein and neurite degeneration are regulated by Gemin3 in spinal muscular atrophy motoneurons |
title_fullStr | Survival motor neuron protein and neurite degeneration are regulated by Gemin3 in spinal muscular atrophy motoneurons |
title_full_unstemmed | Survival motor neuron protein and neurite degeneration are regulated by Gemin3 in spinal muscular atrophy motoneurons |
title_short | Survival motor neuron protein and neurite degeneration are regulated by Gemin3 in spinal muscular atrophy motoneurons |
title_sort | survival motor neuron protein and neurite degeneration are regulated by gemin3 in spinal muscular atrophy motoneurons |
topic | Cellular Neuroscience |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9813745/ https://www.ncbi.nlm.nih.gov/pubmed/36619669 http://dx.doi.org/10.3389/fncel.2022.1054270 |
work_keys_str_mv | AT mirallesmariap survivalmotorneuronproteinandneuritedegenerationareregulatedbygemin3inspinalmuscularatrophymotoneurons AT sansaalba survivalmotorneuronproteinandneuritedegenerationareregulatedbygemin3inspinalmuscularatrophymotoneurons AT beltranmaria survivalmotorneuronproteinandneuritedegenerationareregulatedbygemin3inspinalmuscularatrophymotoneurons AT solerrosam survivalmotorneuronproteinandneuritedegenerationareregulatedbygemin3inspinalmuscularatrophymotoneurons AT garceraana survivalmotorneuronproteinandneuritedegenerationareregulatedbygemin3inspinalmuscularatrophymotoneurons |