Cargando…

Astrocyte-Mediated Neuromodulatory Regulation in Preclinical ALS: A Metadata Analysis

Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease characterized by progressive degradation of motoneurons in the central nervous system (CNS). Astrocytes are key regulators for inflammation and neuromodulatory signaling, both of which contribute to ALS. The study goal was to ascerta...

Descripción completa

Detalles Bibliográficos
Autores principales: Jordan, Kathleen, Murphy, Joseph, Singh, Anjanya, Mitchell, Cassie S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6305074/
https://www.ncbi.nlm.nih.gov/pubmed/30618638
http://dx.doi.org/10.3389/fncel.2018.00491
_version_ 1783382482793529344
author Jordan, Kathleen
Murphy, Joseph
Singh, Anjanya
Mitchell, Cassie S.
author_facet Jordan, Kathleen
Murphy, Joseph
Singh, Anjanya
Mitchell, Cassie S.
author_sort Jordan, Kathleen
collection PubMed
description Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease characterized by progressive degradation of motoneurons in the central nervous system (CNS). Astrocytes are key regulators for inflammation and neuromodulatory signaling, both of which contribute to ALS. The study goal was to ascertain potential temporal changes in astrocyte-mediated neuromodulatory regulation with transgenic ALS model progression: glutamate, GTL-1, GluR1, GluR2, GABA, ChAT activity, VGF, TNFα, aspartate, and IGF-1. We examine neuromodulatory changes in data aggregates from 42 peer-reviewed studies derived from transgenic ALS mixed cell cultures (neurons + astrocytes). For each corresponding experimental time point, the ratio of transgenic to wild type (WT) was found for each compound. ANOVA and a student's t-test were performed to compare disease stages (early, post-onset, and end stage). Glutamate in transgenic SOD1-G93A mixed cell cultures does not change over time (p > 0.05). GLT-1 levels were found to be decreased 23% over WT but only at end-stage (p < 0.05). Glutamate receptors (GluR1, GluR2) in SOD1-G93A were not substantially different from WT, although SOD1-G93A GluR1 decreased by 21% from post-onset to end-stage (p < 0.05). ChAT activity was insignificantly decreased. VGF is decreased throughout ALS (p < 0.05). Aspartate is elevated by 25% in SOD1-G93A but only during end-stage (p < 0.05). TNFα is increased by a dramatic 362% (p < 0.05). Furthermore, principal component analysis identified TNFα as contributing to 55% of the data variance in the first component. Thus, TNFα, which modulates astrocyte regulation via multiple pathways, could be a strategic treatment target. Overall results suggest changes in neuromodulator levels are subtle in SOD1-G93A ALS mixed cell cultures. If excitotoxicity is present as is often presumed, it could be due to ALS cells being more sensitive to small changes in neuromodulation. Hence, seemingly unsubstantial or oscillatory changes in neuromodulators could wreak havoc in ALS cells, resulting in failed microenvironment homeostasis whereby both hyperexcitability and hypoexcitability can coexist. Future work is needed to examine local, spatiotemporal neuromodulatory homeostasis and assess its functional impact in ALS.
format Online
Article
Text
id pubmed-6305074
institution National Center for Biotechnology Information
language English
publishDate 2018
publisher Frontiers Media S.A.
record_format MEDLINE/PubMed
spelling pubmed-63050742019-01-07 Astrocyte-Mediated Neuromodulatory Regulation in Preclinical ALS: A Metadata Analysis Jordan, Kathleen Murphy, Joseph Singh, Anjanya Mitchell, Cassie S. Front Cell Neurosci Neuroscience Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease characterized by progressive degradation of motoneurons in the central nervous system (CNS). Astrocytes are key regulators for inflammation and neuromodulatory signaling, both of which contribute to ALS. The study goal was to ascertain potential temporal changes in astrocyte-mediated neuromodulatory regulation with transgenic ALS model progression: glutamate, GTL-1, GluR1, GluR2, GABA, ChAT activity, VGF, TNFα, aspartate, and IGF-1. We examine neuromodulatory changes in data aggregates from 42 peer-reviewed studies derived from transgenic ALS mixed cell cultures (neurons + astrocytes). For each corresponding experimental time point, the ratio of transgenic to wild type (WT) was found for each compound. ANOVA and a student's t-test were performed to compare disease stages (early, post-onset, and end stage). Glutamate in transgenic SOD1-G93A mixed cell cultures does not change over time (p > 0.05). GLT-1 levels were found to be decreased 23% over WT but only at end-stage (p < 0.05). Glutamate receptors (GluR1, GluR2) in SOD1-G93A were not substantially different from WT, although SOD1-G93A GluR1 decreased by 21% from post-onset to end-stage (p < 0.05). ChAT activity was insignificantly decreased. VGF is decreased throughout ALS (p < 0.05). Aspartate is elevated by 25% in SOD1-G93A but only during end-stage (p < 0.05). TNFα is increased by a dramatic 362% (p < 0.05). Furthermore, principal component analysis identified TNFα as contributing to 55% of the data variance in the first component. Thus, TNFα, which modulates astrocyte regulation via multiple pathways, could be a strategic treatment target. Overall results suggest changes in neuromodulator levels are subtle in SOD1-G93A ALS mixed cell cultures. If excitotoxicity is present as is often presumed, it could be due to ALS cells being more sensitive to small changes in neuromodulation. Hence, seemingly unsubstantial or oscillatory changes in neuromodulators could wreak havoc in ALS cells, resulting in failed microenvironment homeostasis whereby both hyperexcitability and hypoexcitability can coexist. Future work is needed to examine local, spatiotemporal neuromodulatory homeostasis and assess its functional impact in ALS. Frontiers Media S.A. 2018-12-17 /pmc/articles/PMC6305074/ /pubmed/30618638 http://dx.doi.org/10.3389/fncel.2018.00491 Text en Copyright © 2018 Jordan, Murphy, Singh and Mitchell. http://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 Neuroscience
Jordan, Kathleen
Murphy, Joseph
Singh, Anjanya
Mitchell, Cassie S.
Astrocyte-Mediated Neuromodulatory Regulation in Preclinical ALS: A Metadata Analysis
title Astrocyte-Mediated Neuromodulatory Regulation in Preclinical ALS: A Metadata Analysis
title_full Astrocyte-Mediated Neuromodulatory Regulation in Preclinical ALS: A Metadata Analysis
title_fullStr Astrocyte-Mediated Neuromodulatory Regulation in Preclinical ALS: A Metadata Analysis
title_full_unstemmed Astrocyte-Mediated Neuromodulatory Regulation in Preclinical ALS: A Metadata Analysis
title_short Astrocyte-Mediated Neuromodulatory Regulation in Preclinical ALS: A Metadata Analysis
title_sort astrocyte-mediated neuromodulatory regulation in preclinical als: a metadata analysis
topic Neuroscience
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6305074/
https://www.ncbi.nlm.nih.gov/pubmed/30618638
http://dx.doi.org/10.3389/fncel.2018.00491
work_keys_str_mv AT jordankathleen astrocytemediatedneuromodulatoryregulationinpreclinicalalsametadataanalysis
AT murphyjoseph astrocytemediatedneuromodulatoryregulationinpreclinicalalsametadataanalysis
AT singhanjanya astrocytemediatedneuromodulatoryregulationinpreclinicalalsametadataanalysis
AT mitchellcassies astrocytemediatedneuromodulatoryregulationinpreclinicalalsametadataanalysis