40 Years of CSF Toxicity Studies in ALS: What Have We Learnt About ALS Pathophysiology?

Koy Chong  Ng Kee Kwong; Pratap K.  Harbham; Bhuvaneish T.  Selvaraj; Jenna Gregory; Suvankar  Pal; Giles E.  Hardingham; Siddharthan Chandran; Arpan R. Mehta

doi:10.3389/fnmol.2021.647895

40 Years of CSF Toxicity Studies in ALS: What Have We Learnt About ALS Pathophysiology?

Koy Chong Ng Kee Kwong, Pratap K. Harbham, Bhuvaneish T. Selvaraj, Jenna Gregory, Suvankar Pal, Giles E. Hardingham, Siddharthan Chandran, Arpan R. Mehta^* (Corresponding Author)

^*Corresponding author for this work

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Abstract

Based on early evidence of in vitro neurotoxicity following exposure to serum derived from patients with amyotrophic lateral sclerosis (ALS), several studies have attempted to explore whether cerebrospinal fluid (CSF) obtained from people with ALS could possess similar properties. Although initial findings proved inconclusive, it is now increasingly recognized that ALS-CSF may exert toxicity both in vitro and in vivo. Nevertheless, the mechanism underlying CSF-induced neurodegeneration remains unclear. This review aims to summarize the 40-year long history of CSF toxicity studies in ALS, while discussing the various mechanisms that have been proposed, including glutamate excitotoxicity, proteotoxicity and oxidative stress. Furthermore, we consider the potential implications of a toxic CSF circulatory system in the pathophysiology of ALS, and also assess its significance in the context of current ALS research.

Original language	English
Article number	647895
Number of pages	11
Journal	Frontiers in Molecular Neuroscience
Volume	14
DOIs	https://doi.org/10.3389/fnmol.2021.647895
Publication status	Published - 18 Mar 2021

Bibliographical note

AM is a Lady Edith Wolfson Clinical Fellow and is jointly funded by the Medical Research Council (MRC) and the Motor Neurone Disease Association (MR/R001162/1). He also acknowledges support from the Rowling Scholars scheme, administered by the Anne Rowling Regenerative Neurology Clinic (ARRNC), University of Edinburgh, and a seedcorn grant from The Chief Scientist Office and the RS Macdonald Charitable Trust via the Scottish Neurological Research Fund, administered by the University of St Andrews. The Hardingham and Chandran laboratories are supported by the Euan MacDonald Centre for Motor Neurone Disease Research, and the UK Dementia Research Institute (DRI), which receives its funding from UK DRI Ltd., funded by the MRC, Alzheimer’s Society and Alzheimer’s Research UK.

Keywords

amyotrophic lateral sclerosis
, cerebrospinal fluid
motor neuron disease
neurodegeneration
pathophysiology
toxicity

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Copyright © 2021 Ng Kee Kwong, Harbham, Selvaraj, Gregory, Pal, Hardingham, Chandran and Mehta. 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. https://creativecommons.org/licenses/by/4.0/
Final published version, 2.02 MBLicence: CC BY

Cite this

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title = "40 Years of CSF Toxicity Studies in ALS: What Have We Learnt About ALS Pathophysiology?",

abstract = "Based on early evidence of in vitro neurotoxicity following exposure to serum derived from patients with amyotrophic lateral sclerosis (ALS), several studies have attempted to explore whether cerebrospinal fluid (CSF) obtained from people with ALS could possess similar properties. Although initial findings proved inconclusive, it is now increasingly recognized that ALS-CSF may exert toxicity both in vitro and in vivo. Nevertheless, the mechanism underlying CSF-induced neurodegeneration remains unclear. This review aims to summarize the 40-year long history of CSF toxicity studies in ALS, while discussing the various mechanisms that have been proposed, including glutamate excitotoxicity, proteotoxicity and oxidative stress. Furthermore, we consider the potential implications of a toxic CSF circulatory system in the pathophysiology of ALS, and also assess its significance in the context of current ALS research.",

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author = "{Ng Kee Kwong}, {Koy Chong} and Harbham, {Pratap K.} and Selvaraj, {Bhuvaneish T.} and Jenna Gregory and Suvankar Pal and Hardingham, {Giles E.} and Siddharthan Chandran and Mehta, {Arpan R.}",

note = "AM is a Lady Edith Wolfson Clinical Fellow and is jointly funded by the Medical Research Council (MRC) and the Motor Neurone Disease Association (MR/R001162/1). He also acknowledges support from the Rowling Scholars scheme, administered by the Anne Rowling Regenerative Neurology Clinic (ARRNC), University of Edinburgh, and a seedcorn grant from The Chief Scientist Office and the RS Macdonald Charitable Trust via the Scottish Neurological Research Fund, administered by the University of St Andrews. The Hardingham and Chandran laboratories are supported by the Euan MacDonald Centre for Motor Neurone Disease Research, and the UK Dementia Research Institute (DRI), which receives its funding from UK DRI Ltd., funded by the MRC, Alzheimer{\textquoteright}s Society and Alzheimer{\textquoteright}s Research UK. ",

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AU - Ng Kee Kwong, Koy Chong

AU - Harbham, Pratap K.

AU - Selvaraj, Bhuvaneish T.

AU - Gregory, Jenna

AU - Pal, Suvankar

AU - Hardingham, Giles E.

AU - Chandran, Siddharthan

AU - Mehta, Arpan R.

N1 - AM is a Lady Edith Wolfson Clinical Fellow and is jointly funded by the Medical Research Council (MRC) and the Motor Neurone Disease Association (MR/R001162/1). He also acknowledges support from the Rowling Scholars scheme, administered by the Anne Rowling Regenerative Neurology Clinic (ARRNC), University of Edinburgh, and a seedcorn grant from The Chief Scientist Office and the RS Macdonald Charitable Trust via the Scottish Neurological Research Fund, administered by the University of St Andrews. The Hardingham and Chandran laboratories are supported by the Euan MacDonald Centre for Motor Neurone Disease Research, and the UK Dementia Research Institute (DRI), which receives its funding from UK DRI Ltd., funded by the MRC, Alzheimer’s Society and Alzheimer’s Research UK.

PY - 2021/3/18

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N2 - Based on early evidence of in vitro neurotoxicity following exposure to serum derived from patients with amyotrophic lateral sclerosis (ALS), several studies have attempted to explore whether cerebrospinal fluid (CSF) obtained from people with ALS could possess similar properties. Although initial findings proved inconclusive, it is now increasingly recognized that ALS-CSF may exert toxicity both in vitro and in vivo. Nevertheless, the mechanism underlying CSF-induced neurodegeneration remains unclear. This review aims to summarize the 40-year long history of CSF toxicity studies in ALS, while discussing the various mechanisms that have been proposed, including glutamate excitotoxicity, proteotoxicity and oxidative stress. Furthermore, we consider the potential implications of a toxic CSF circulatory system in the pathophysiology of ALS, and also assess its significance in the context of current ALS research.

AB - Based on early evidence of in vitro neurotoxicity following exposure to serum derived from patients with amyotrophic lateral sclerosis (ALS), several studies have attempted to explore whether cerebrospinal fluid (CSF) obtained from people with ALS could possess similar properties. Although initial findings proved inconclusive, it is now increasingly recognized that ALS-CSF may exert toxicity both in vitro and in vivo. Nevertheless, the mechanism underlying CSF-induced neurodegeneration remains unclear. This review aims to summarize the 40-year long history of CSF toxicity studies in ALS, while discussing the various mechanisms that have been proposed, including glutamate excitotoxicity, proteotoxicity and oxidative stress. Furthermore, we consider the potential implications of a toxic CSF circulatory system in the pathophysiology of ALS, and also assess its significance in the context of current ALS research.

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KW - toxicity

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JO - Frontiers in Molecular Neuroscience

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40 Years of CSF Toxicity Studies in ALS: What Have We Learnt About ALS Pathophysiology?

Abstract

Bibliographical note

Keywords

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