Dynamic Meta-Analysis as a Therapeutic Prediction Tool for Amyotrophic Lateral Sclerosis

Mitchell, Cassie S.; Lee, Robert H.

doi:10.5772/32384

Cited by 5 publications

(8 citation statements)

References 58 publications

(56 reference statements)

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“…Asides from approaches using MINs, which have been the subject of this review, several studies have applied mathematical modelling to attempt to understand the pathology in terms of relationships between high-order disease concepts such as “genetic damage”, “necro-apoptosis”, “calcium homeostasis”, “cellular respiration”, and other processes [141,142], whereas others have mathematically modelled clinical features in order to better predict disease progression in each patient [143,144]. MIN approaches may ultimately feed into higher order and clinical models, for example if they are used to better define molecular pathways or molecular biomarkers.…”

Section: Discussionmentioning

confidence: 99%

Personalized Medicine and Molecular Interaction Networks in Amyotrophic Lateral Sclerosis (ALS): Current Knowledge

Morgan

Duguez

Duddy

2018

JPM

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Multiple genes and mechanisms of pathophysiology have been implicated in amyotrophic lateral sclerosis (ALS), suggesting it is a complex systemic disease. With this in mind, applying personalized medicine (PM) approaches to tailor treatment pipelines for ALS patients may be necessary. The modelling and analysis of molecular interaction networks could represent valuable resources in defining ALS-associated pathways and discovering novel therapeutic targets. Here we review existing omics datasets and analytical approaches, in order to consider how molecular interaction networks could improve our understanding of the molecular pathophysiology of this fatal neuromuscular disorder.

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Section: Discussionmentioning

confidence: 99%

Personalized Medicine and Molecular Interaction Networks in Amyotrophic Lateral Sclerosis (ALS): Current Knowledge

Morgan

Duguez

Duddy

2018

JPM

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“…Ca2 + increases could come from a variety of mechanisms beyond direct or significant changes in neuromodulatory transmission. As proposed in prior work (Mitchell and Lee, 2012; Mitchell et al, 2015b; Hollinger et al, 2016; Kim et al, 2016), failed homeostasis in nearly ten different major pathways could explain how a variety of different perturbations that result in ALS and identified homeostatic regulatory instability. Ca2 + regulation is also greatly impacted by changes in energetic pathways (namely mitochondria and endoplasmic reticulum Ca2 + stores) and oxidative stress (Bond et al, 2018), and to a lesser degree, by apoptotic signaling (Irvin et al, 2015).…”

Section: Discussionmentioning

confidence: 82%

“…Thus, even small or seemingly insignificant oscillatory increases or decreases in neuromodulators, which could easily be rectified with compensatory regulation in normal cells, could potentially wreak havoc in ALS cells. In fact, as discussed in more detail in the Section Astrocyte GluR as a Potential Pre-onset ALS Treatment Target, motoneurons are mathematically and functionally more susceptible to such instability (Mitchell and Lee, 2012; Irvin et al, 2015). Other recent work has also illustrated that motoneuron microcircuits are more prone to homeostatic dysregulation (Brownstone and Lancelin, 2018).…”

Section: Discussionmentioning

confidence: 99%

“…Motoneurons are more prone to instability due to their long length (Mitchell and Lee, 2012), which requires transport and signaling over very long distances in the axon. Any delays or offset in signaling within cells or even between cells, such as between neurons and astrocytes, could contribute to oscillatory instability.…”

Section: Discussionmentioning

confidence: 99%

“…The oscillations seen in CNS experimental data, and especially Ca2 +, support the homeostatic instability theory (Irvin et al, 2015) of ALS. Given the very small margin of error for homeostatic regulation in motoneurons (Mitchell and Lee, 2012), localized examination of Ca2 + with sufficient spatio-temporal resolution in the future could provide key evidence for experimentally confirming the contributions, or lack thereof, of neuromodulatory regulation mechanisms in neurons and astrocytes.…”

Section: Discussionmentioning

confidence: 99%

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

Jordan

Murphy

Singh

et al. 2018

Front. Cell. Neurosci.

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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.

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Time course of alterations in adult spinal motoneuron properties in the SOD1(G93A) mouse model of ALS

Huh

Heckman

Manuel

2020

Preprint

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Author contributionConceptualization: S.H., C.J.H., and M.M.; Methodology: S.H., C.J.H., and M.M.; Investigation: S.H.; Formal analysis: S.H. and M.M.; Software: M.M.; Visualization: S.H. and M.M.; Writing -Original Draft: S.H.; Writing -Review & Editing: S.H., C.J.H., and M.M.; S.H., C.J.H., and M.M. approved final version of manuscript. AbstractAlthough ALS is an adult-onset neurodegenerative disease, motoneuron electrical properties are already altered during embryonic development. Motoneurons must therefore exhibit remarkable capacity for homeostatic regulation to maintain a normal motor output for most of the life of the patient. In the present paper, we demonstrate how maintaining homeostasis could come at a very high cost. We studied the excitability of spinal motoneurons from young adult SOD1(G93A) mice to end-stage. Initially homeostasis is highly successful in maintaining their overall excitability. This initial success, however, is achieved by pushing some cells far above the normal range of passive and active conductances. As the disease progresses, both passive and active conductances shrink below normal values in the surviving cells. This shrinkage may thus promote survival, implying the previously large values contribute to degeneration. These results support the hypothesis that motoneuronal homeostasis may be "hyper-vigilant" in ALS, and a source of accumulating stress.

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Dynamic Meta-Analysis as a Therapeutic Prediction Tool for Amyotrophic Lateral Sclerosis

Cited by 5 publications

References 58 publications

Personalized Medicine and Molecular Interaction Networks in Amyotrophic Lateral Sclerosis (ALS): Current Knowledge

Personalized Medicine and Molecular Interaction Networks in Amyotrophic Lateral Sclerosis (ALS): Current Knowledge

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

Time course of alterations in adult spinal motoneuron properties in the SOD1(G93A) mouse model of ALS

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