α-Methyl-α-phenylsuccinimide ameliorates neurodegeneration in a C. elegans model of TDP-43 proteinopathy
The antiepileptic drug ethosuximide has recently been shown to be neuroprotective in various Caenorhabditis elegans and rodent neurodegeneration models. It is therefore a promising repurposing candidate for the treatment of multiple neurodegenerative diseases. However, high concentrations of the dru...
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Elsevier
2018-10-01
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Series: | Neurobiology of Disease |
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Online Access: | http://www.sciencedirect.com/science/article/pii/S096999611830192X |
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Article |
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DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Shi Quan Wong Matthew G. Pontifex Marie M. Phelan Chandra Pidathala Brian C. Kraemer Jeff W. Barclay Neil G. Berry Paul M. O'Neill Robert D. Burgoyne Alan Morgan |
spellingShingle |
Shi Quan Wong Matthew G. Pontifex Marie M. Phelan Chandra Pidathala Brian C. Kraemer Jeff W. Barclay Neil G. Berry Paul M. O'Neill Robert D. Burgoyne Alan Morgan α-Methyl-α-phenylsuccinimide ameliorates neurodegeneration in a C. elegans model of TDP-43 proteinopathy Neurobiology of Disease Neurodegeneration Amyotrophic lateral sclerosis Frontotemporal lobar degeneration Ethosuximide Methsuximide Desmethylmethsuximide |
author_facet |
Shi Quan Wong Matthew G. Pontifex Marie M. Phelan Chandra Pidathala Brian C. Kraemer Jeff W. Barclay Neil G. Berry Paul M. O'Neill Robert D. Burgoyne Alan Morgan |
author_sort |
Shi Quan Wong |
title |
α-Methyl-α-phenylsuccinimide ameliorates neurodegeneration in a C. elegans model of TDP-43 proteinopathy |
title_short |
α-Methyl-α-phenylsuccinimide ameliorates neurodegeneration in a C. elegans model of TDP-43 proteinopathy |
title_full |
α-Methyl-α-phenylsuccinimide ameliorates neurodegeneration in a C. elegans model of TDP-43 proteinopathy |
title_fullStr |
α-Methyl-α-phenylsuccinimide ameliorates neurodegeneration in a C. elegans model of TDP-43 proteinopathy |
title_full_unstemmed |
α-Methyl-α-phenylsuccinimide ameliorates neurodegeneration in a C. elegans model of TDP-43 proteinopathy |
title_sort |
α-methyl-α-phenylsuccinimide ameliorates neurodegeneration in a c. elegans model of tdp-43 proteinopathy |
publisher |
Elsevier |
series |
Neurobiology of Disease |
issn |
1095-953X |
publishDate |
2018-10-01 |
description |
The antiepileptic drug ethosuximide has recently been shown to be neuroprotective in various Caenorhabditis elegans and rodent neurodegeneration models. It is therefore a promising repurposing candidate for the treatment of multiple neurodegenerative diseases. However, high concentrations of the drug are required for its protective effects in animal models, which may impact on its translational potential and impede the identification of its molecular mechanism of action. Therefore, we set out to develop more potent neuroprotective lead compounds based on ethosuximide as a starting scaffold. Chemoinformatic approaches were used to identify compounds with structural similarity to ethosuximide and to prioritise these based on good predicated blood-brain barrier permeability and C. elegans bioaccumulation properties. Selected compounds were initially screened for anti-convulsant activity in a C. elegans pentylenetetrazol-induced seizure assay, as a rapid primary readout of bioactivity; and then assessed for neuroprotective properties in a C. elegans TDP-43 proteinopathy model based on pan-neuronal expression of human A315T mutant TDP-43. The most potent compound screened, α-methyl-α-phenylsuccinimide (MPS), ameliorated the locomotion defects and extended the shortened lifespan of TDP-43 mutant worms. MPS also directly protected against neurodegeneration by reducing the number of neuronal breaks and cell body losses in GFP-labelled GABAergic motor neurons. Importantly, optimal neuroprotection was exhibited by external application of 50 μM MPS, compared to 8 mM for ethosuximide. This greater potency of MPS was not due to bioaccumulation to higher internal levels within the worm, based on 1H-nuclear magnetic resonance analysis. Like ethosuximide, the activity of MPS was abolished by mutation of the evolutionarily conserved FOXO transcription factor, daf-16, suggesting that both compounds act via the same neuroprotective pathway(s).In conclusion, we have revealed a novel neuroprotective activity of MPS that is >100-fold more potent than ethosuximide. This increased potency will facilitate future biochemical studies to identify the direct molecular target(s) of both compounds, as we have shown here that they share a common downstream DAF-16-dependent mechanism of action. Furthermore, MPS is the active metabolite of another approved antiepileptic drug, methsuximide. Therefore, methsuximide may have repurposing potential for treatment of TDP-43 proteinopathies and possibly other human neurodegenerative diseases. |
topic |
Neurodegeneration Amyotrophic lateral sclerosis Frontotemporal lobar degeneration Ethosuximide Methsuximide Desmethylmethsuximide |
url |
http://www.sciencedirect.com/science/article/pii/S096999611830192X |
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doaj-a0a5900ed9fb48d482ef1008482443922021-03-22T12:46:43ZengElsevierNeurobiology of Disease1095-953X2018-10-011184054α-Methyl-α-phenylsuccinimide ameliorates neurodegeneration in a C. elegans model of TDP-43 proteinopathyShi Quan Wong0Matthew G. Pontifex1Marie M. Phelan2Chandra Pidathala3Brian C. Kraemer4Jeff W. Barclay5Neil G. Berry6Paul M. O'Neill7Robert D. Burgoyne8Alan Morgan9Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool, UKDepartment of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool, UKDepartment of Biochemistry, Institute of Integrative Biology, University of Liverpool, Liverpool, UKDepartment of Chemistry, University of Liverpool, Liverpool, UKGeriatrics Research Education and Clinical Center, Seattle Veterans Affairs Puget Sound Health Care System, University of Washington Department of Medicine, Seattle, WA 98108, USADepartment of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool, UKDepartment of Chemistry, University of Liverpool, Liverpool, UKDepartment of Chemistry, University of Liverpool, Liverpool, UKDepartment of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool, UKDepartment of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool, UK; Corresponding author.The antiepileptic drug ethosuximide has recently been shown to be neuroprotective in various Caenorhabditis elegans and rodent neurodegeneration models. It is therefore a promising repurposing candidate for the treatment of multiple neurodegenerative diseases. However, high concentrations of the drug are required for its protective effects in animal models, which may impact on its translational potential and impede the identification of its molecular mechanism of action. Therefore, we set out to develop more potent neuroprotective lead compounds based on ethosuximide as a starting scaffold. Chemoinformatic approaches were used to identify compounds with structural similarity to ethosuximide and to prioritise these based on good predicated blood-brain barrier permeability and C. elegans bioaccumulation properties. Selected compounds were initially screened for anti-convulsant activity in a C. elegans pentylenetetrazol-induced seizure assay, as a rapid primary readout of bioactivity; and then assessed for neuroprotective properties in a C. elegans TDP-43 proteinopathy model based on pan-neuronal expression of human A315T mutant TDP-43. The most potent compound screened, α-methyl-α-phenylsuccinimide (MPS), ameliorated the locomotion defects and extended the shortened lifespan of TDP-43 mutant worms. MPS also directly protected against neurodegeneration by reducing the number of neuronal breaks and cell body losses in GFP-labelled GABAergic motor neurons. Importantly, optimal neuroprotection was exhibited by external application of 50 μM MPS, compared to 8 mM for ethosuximide. This greater potency of MPS was not due to bioaccumulation to higher internal levels within the worm, based on 1H-nuclear magnetic resonance analysis. Like ethosuximide, the activity of MPS was abolished by mutation of the evolutionarily conserved FOXO transcription factor, daf-16, suggesting that both compounds act via the same neuroprotective pathway(s).In conclusion, we have revealed a novel neuroprotective activity of MPS that is >100-fold more potent than ethosuximide. This increased potency will facilitate future biochemical studies to identify the direct molecular target(s) of both compounds, as we have shown here that they share a common downstream DAF-16-dependent mechanism of action. Furthermore, MPS is the active metabolite of another approved antiepileptic drug, methsuximide. Therefore, methsuximide may have repurposing potential for treatment of TDP-43 proteinopathies and possibly other human neurodegenerative diseases.http://www.sciencedirect.com/science/article/pii/S096999611830192XNeurodegenerationAmyotrophic lateral sclerosisFrontotemporal lobar degenerationEthosuximideMethsuximideDesmethylmethsuximide |