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

Kathleen Jordan,Cassie S Mitchell,Anjanya Singh,Joseph Murphy

doi:10.3389/fncel.2018.00491

Abstract

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.

Highlights

Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease characterized by the progressive degradation of motoneurons, which results in muscle paralysis, respiratory failure, and death
The metadata analysis results do not paint a picture of widespread, overt glutamate-mediated excitotoxicity in preclinical ALS as measured in mixed cell cultures
The key neuromodulators, namely glutamate, glutamate receptors, and transports, gamma-Aminobutyric acid (GABA), and choline acetyltransferase (ChAT), showed no so significant changes in ALS compared to wild type (WT) or significant changes over the course of ALS disease progression

Summary

Introduction

Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease characterized by the progressive degradation of motoneurons, which results in muscle paralysis, respiratory failure, and death. Because the multi-factorial nature of ALS is difficult to study in humans, experimental mouse models are critical for etiological and treatment elucidation. The superoxide dismutase 1 glycine 93 to alanine (SOD1-G93A) transgenic mouse is currently the predominant means of investigating the preclinical pathophysiology of ALS (Pfohl et al, 2015) because it of its rich publication history and reproducibility. ALS pathophysiology has multi-scalar disturbances that impact numerous processes, including inflammation, apoptosis, energetics, excitability, genetic transcription, cellular chemistry, oxidative stress, proteomics, and systemic function (Irvin et al, 2015; Kim et al, 2016). While ALS is a motoneuron disease, non-neuronal tissues are affected, including astrocytes, glia, and muscle. Inflammation, a process that is predominantly driven by non-neural tissue, is the most published etiology examined in SOD1-G93A ALS mice (Kim et al, 2016)

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