Integrated elemental analysis supports targeting copper perturbations as a therapeutic strategy in multiple sclerosis.

Hilton, JBW; Kysenius, K; Liddell, JR; Mercer, SW; Rautengarten, C; Hare, DJ; Buncic, G; Paul, B; Murray, SS; McLean, CA; Kilpatrick, TJ; Beckman, JS; Ayton, S; Bush, AI; White, AR; Roberts, BR; Donnelly, PS; Crouch, PJ

Integrated elemental analysis supports targeting copper perturbations as a therapeutic strategy in multiple sclerosis.

Hilton, JBW Kysenius, K Liddell, JR Mercer, SW Rautengarten, C Hare, DJ Buncic, G Paul, B Murray, SS McLean, CA Kilpatrick, TJ Beckman, JS Ayton, S Bush, AI White, AR Roberts, BR Donnelly, PS Crouch, PJ

Permalink

Publisher:: Elsevier
Publication Type:: Journal Article
Citation:: Neurotherapeutics, 2024, 21, (5), pp. e00432
Issue Date:: 2024-09

Open Access

Copyright Clearance Process

Recently Added
In Progress
Open Access

This item is open access.

Adobe PDF

Download Published versionAdobe PDF (2.67 MB)

View on publisher's site

View statistics

Full metadata record

Field	Value	Language
dc.contributor.author	Hilton, JBW
dc.contributor.author	Kysenius, K
dc.contributor.author	Liddell, JR
dc.contributor.author	Mercer, SW
dc.contributor.author	Rautengarten, C
dc.contributor.author	Hare, DJ
dc.contributor.author	Buncic, G
dc.contributor.author	Paul, B
dc.contributor.author	Murray, SS
dc.contributor.author	McLean, CA
dc.contributor.author	Kilpatrick, TJ
dc.contributor.author	Beckman, JS
dc.contributor.author	Ayton, S
dc.contributor.author	Bush, AI
dc.contributor.author	White, AR
dc.contributor.author	Roberts, BR
dc.contributor.author	Donnelly, PS
dc.contributor.author	Crouch, PJ
dc.date.accessioned	2025-01-02T03:58:43Z
dc.date.available	2024-08-07
dc.date.available	2025-01-02T03:58:43Z
dc.date.issued	2024-09
dc.identifier.citation	Neurotherapeutics, 2024, 21, (5), pp. e00432
dc.identifier.issn	1933-7213
dc.identifier.issn	1878-7479
dc.identifier.uri	http://hdl.handle.net/10453/182799
dc.description.abstract	Multiple sclerosis (MS) is a debilitating affliction of the central nervous system (CNS) that involves demyelination of neuronal axons and neurodegeneration resulting in disability that becomes more pronounced in progressive forms of the disease. The involvement of neurodegeneration in MS underscores the need for effective neuroprotective approaches necessitating identification of new therapeutic targets. Herein, we applied an integrated elemental analysis workflow to human MS-affected spinal cord tissue utilising multiple inductively coupled plasma-mass spectrometry methodologies. These analyses revealed shifts in atomic copper as a notable aspect of disease. Complementary gene expression and biochemical analyses demonstrated that changes in copper levels coincided with altered expression of copper handling genes and downstream functionality of cuproenzymes. Copper-related problems observed in the human MS spinal cord were largely reproduced in the experimental autoimmune encephalomyelitis (EAE) mouse model during the acute phase of disease characterised by axonal demyelination, lesion formation, and motor neuron loss. Treatment of EAE mice with the CNS-permeant copper modulating compound CuII(atsm) resulted in recovery of cuproenzyme function, improved myelination and lesion volume, and neuroprotection. These findings support targeting copper perturbations as a therapeutic strategy for MS with CuII(atsm) showing initial promise.
dc.format	Print-Electronic
dc.language	eng
dc.publisher	Elsevier
dc.relation.ispartof	Neurotherapeutics
dc.relation.isbasedon	10.1016/j.neurot.2024.e00432
dc.rights	info:eu-repo/semantics/openAccess
dc.subject	1109 Neurosciences, 1115 Pharmacology and Pharmaceutical Sciences, 1117 Public Health and Health Services
dc.subject.classification	Neurology & Neurosurgery
dc.subject.classification	3209 Neurosciences
dc.subject.classification	3214 Pharmacology and pharmaceutical sciences
dc.subject.classification	5202 Biological psychology
dc.subject.mesh	Copper
dc.subject.mesh	Animals
dc.subject.mesh	Encephalomyelitis, Autoimmune, Experimental
dc.subject.mesh	Multiple Sclerosis
dc.subject.mesh	Mice
dc.subject.mesh	Humans
dc.subject.mesh	Female
dc.subject.mesh	Spinal Cord
dc.subject.mesh	Mice, Inbred C57BL
dc.subject.mesh	Organometallic Compounds
dc.subject.mesh	Coordination Complexes
dc.subject.mesh	Thiosemicarbazones
dc.subject.mesh	Spinal Cord
dc.subject.mesh	Animals
dc.subject.mesh	Mice, Inbred C57BL
dc.subject.mesh	Humans
dc.subject.mesh	Mice
dc.subject.mesh	Multiple Sclerosis
dc.subject.mesh	Encephalomyelitis, Autoimmune, Experimental
dc.subject.mesh	Copper
dc.subject.mesh	Organometallic Compounds
dc.subject.mesh	Thiosemicarbazones
dc.subject.mesh	Female
dc.subject.mesh	Coordination Complexes
dc.subject.mesh	Copper
dc.subject.mesh	Animals
dc.subject.mesh	Encephalomyelitis, Autoimmune, Experimental
dc.subject.mesh	Multiple Sclerosis
dc.subject.mesh	Mice
dc.subject.mesh	Humans
dc.subject.mesh	Female
dc.subject.mesh	Spinal Cord
dc.subject.mesh	Mice, Inbred C57BL
dc.subject.mesh	Organometallic Compounds
dc.subject.mesh	Coordination Complexes
dc.subject.mesh	Thiosemicarbazones
dc.title	Integrated elemental analysis supports targeting copper perturbations as a therapeutic strategy in multiple sclerosis.
dc.type	Journal Article
utslib.citation.volume	21
utslib.location.activity	United States
utslib.for	1109 Neurosciences
utslib.for	1115 Pharmacology and Pharmaceutical Sciences
utslib.for	1117 Public Health and Health Services
pubs.organisational-group	University of Technology Sydney
pubs.organisational-group	University of Technology Sydney/Faculty of Science
pubs.organisational-group	University of Technology Sydney/Faculty of Science/School of Mathematical and Physical Sciences
utslib.copyright.status	open_access	*
dc.rights.license	This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0). To view a copy of this license, visit https://creativecommons.org/licenses/by/4.0/
dc.date.updated	2025-01-02T03:58:41Z
pubs.issue	5
pubs.publication-status	Published
pubs.volume	21
utslib.citation.issue	5

Abstract:

Multiple sclerosis (MS) is a debilitating affliction of the central nervous system (CNS) that involves demyelination of neuronal axons and neurodegeneration resulting in disability that becomes more pronounced in progressive forms of the disease. The involvement of neurodegeneration in MS underscores the need for effective neuroprotective approaches necessitating identification of new therapeutic targets. Herein, we applied an integrated elemental analysis workflow to human MS-affected spinal cord tissue utilising multiple inductively coupled plasma-mass spectrometry methodologies. These analyses revealed shifts in atomic copper as a notable aspect of disease. Complementary gene expression and biochemical analyses demonstrated that changes in copper levels coincided with altered expression of copper handling genes and downstream functionality of cuproenzymes. Copper-related problems observed in the human MS spinal cord were largely reproduced in the experimental autoimmune encephalomyelitis (EAE) mouse model during the acute phase of disease characterised by axonal demyelination, lesion formation, and motor neuron loss. Treatment of EAE mice with the CNS-permeant copper modulating compound CuII(atsm) resulted in recovery of cuproenzyme function, improved myelination and lesion volume, and neuroprotection. These findings support targeting copper perturbations as a therapeutic strategy for MS with CuII(atsm) showing initial promise.

Please use this identifier to cite or link to this item:

http://hdl.handle.net/10453/182799