Parkinson-like wild-type superoxide dismutase 1 pathology induces nigral dopamine neuron degeneration in a novel murine model.

Abdeen, AH; Trist, BG; Nikseresht, S; Harwood, R; Roudeau, S; Rowlands, BD; Kreilaus, F; Cottam, V; Mor, D; Richardson, M; Siciliano, J; Forkgen, J; Schaffer, G; Genoud, S; Li, AA; Proschogo, N; Antonio, B; Falkenberg, G; Brueckner, D; Kysenius, K; Liddell, JR; Fat, SCM; Wu, S; Fifita, J; Lockwood, TE; Bishop, DP; Blair, I; Ortega, R; Crouch, PJ; Double, KL

Parkinson-like wild-type superoxide dismutase 1 pathology induces nigral dopamine neuron degeneration in a novel murine model.

Abdeen, AH Trist, BG Nikseresht, S Harwood, R Roudeau, S Rowlands, BD Kreilaus, F Cottam, V Mor, D Richardson, M Siciliano, J Forkgen, J Schaffer, G Genoud, S Li, AA Proschogo, N Antonio, B Falkenberg, G Brueckner, D Kysenius, K Liddell, JR Fat, SCM Wu, S Fifita, J Lockwood, TE Bishop, DP Blair, I Ortega, R Crouch, PJ Double, KL

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Publisher:: Springer Nature
Publication Type:: Journal Article
Citation:: Acta Neuropathol, 2025, 149, (1), pp. 22
Issue Date:: 2025-03-05

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Field	Value	Language
dc.contributor.author	Abdeen, AH
dc.contributor.author	Trist, BG
dc.contributor.author	Nikseresht, S
dc.contributor.author	Harwood, R
dc.contributor.author	Roudeau, S
dc.contributor.author	Rowlands, BD
dc.contributor.author	Kreilaus, F
dc.contributor.author	Cottam, V
dc.contributor.author	Mor, D
dc.contributor.author	Richardson, M
dc.contributor.author	Siciliano, J
dc.contributor.author	Forkgen, J
dc.contributor.author	Schaffer, G
dc.contributor.author	Genoud, S
dc.contributor.author	Li, AA
dc.contributor.author	Proschogo, N
dc.contributor.author	Antonio, B
dc.contributor.author	Falkenberg, G
dc.contributor.author	Brueckner, D
dc.contributor.author	Kysenius, K
dc.contributor.author	Liddell, JR
dc.contributor.author	Fat, SCM
dc.contributor.author	Wu, S
dc.contributor.author	Fifita, J
dc.contributor.author	Lockwood, TE
dc.contributor.author	Bishop, DP
dc.contributor.author	Blair, I
dc.contributor.author	Ortega, R
dc.contributor.author	Crouch, PJ
dc.contributor.author	Double, KL
dc.date.accessioned	2025-04-03T23:11:06Z
dc.date.available	2025-02-12
dc.date.available	2025-04-03T23:11:06Z
dc.date.issued	2025-03-05
dc.identifier.citation	Acta Neuropathol, 2025, 149, (1), pp. 22
dc.identifier.issn	0001-6322
dc.identifier.issn	1432-0533
dc.identifier.uri	http://hdl.handle.net/10453/186576
dc.description.abstract	Atypical wild-type superoxide dismutase 1 (SOD1) protein misfolding and deposition occurs specifically within the degenerating substantia nigra pars compacta (SNc) in Parkinson disease. Mechanisms driving the formation of this pathology and relationship with SNc dopamine neuron health are yet to be fully understood. We applied proteomic mass spectrometry and synchrotron-based biometal quantification to post-mortem brain tissues from the SNc of Parkinson disease patients and age-matched controls to uncover key factors underlying the formation of wild-type SOD1 pathology in this disorder. We also engineered two of these factors - brain copper deficiency and upregulated SOD1 protein levels - into a novel mouse strain, termed the SOCK mouse, to verify their involvement in the development of Parkinson-like wild-type SOD1 pathology and their impact on dopamine neuron health. Soluble SOD1 protein in the degenerating Parkinson disease SNc exhibited altered post-translational modifications, which may underlie changes to the enzymatic activity and aggregation of the protein in this region. These include decreased copper binding, dysregulation of physiological glycosylation, and atypical oxidation and glycation of key SOD1 amino acid residues. We demonstrated that the biochemical profile introduced in SOCK mice promotes the same post-translational modifications and the development of Parkinson-like wild-type SOD1 pathology in the midbrain and cortex. This pathology accumulates progressively with age and is accompanied by nigrostriatal degeneration and dysfunction, which occur in the absence of α-synuclein deposition. These mice do not exhibit weight loss nor spinal cord motor neuron degeneration, distinguishing them from transgenic mutant SOD1 mouse models. This study provides the first in vivo evidence that mismetallation and altered post-translational modifications precipitates wild-type SOD1 misfolding, dysfunction, and deposition in the Parkinson disease brain, which may contribute to SNc dopamine neuron degeneration. Our data position this pathology as a novel drug target for this disorder, with a particular focus on therapies capable of correcting alterations to SOD1 post-translational modifications.
dc.format	Electronic
dc.language	eng
dc.publisher	Springer Nature
dc.relation	http://purl.org/au-research/grants/arc/DP230101740
dc.relation.ispartof	Acta Neuropathol
dc.relation.isbasedon	10.1007/s00401-025-02859-6
dc.rights	info:eu-repo/semantics/openAccess
dc.subject	1103 Clinical Sciences, 1109 Neurosciences
dc.subject.classification	Neurology & Neurosurgery
dc.subject.classification	3209 Neurosciences
dc.subject.mesh	Animals
dc.subject.mesh	Superoxide Dismutase-1
dc.subject.mesh	Dopaminergic Neurons
dc.subject.mesh	Disease Models, Animal
dc.subject.mesh	Substantia Nigra
dc.subject.mesh	Mice, Transgenic
dc.subject.mesh	Mice
dc.subject.mesh	Humans
dc.subject.mesh	Nerve Degeneration
dc.subject.mesh	Male
dc.subject.mesh	Parkinson Disease
dc.subject.mesh	Female
dc.subject.mesh	Mice, Inbred C57BL
dc.subject.mesh	Copper
dc.subject.mesh	Aged
dc.subject.mesh	Substantia Nigra
dc.subject.mesh	Animals
dc.subject.mesh	Mice, Inbred C57BL
dc.subject.mesh	Mice, Transgenic
dc.subject.mesh	Humans
dc.subject.mesh	Mice
dc.subject.mesh	Parkinson Disease
dc.subject.mesh	Disease Models, Animal
dc.subject.mesh	Nerve Degeneration
dc.subject.mesh	Copper
dc.subject.mesh	Aged
dc.subject.mesh	Female
dc.subject.mesh	Male
dc.subject.mesh	Dopaminergic Neurons
dc.subject.mesh	Superoxide Dismutase-1
dc.subject.mesh	Animals
dc.subject.mesh	Superoxide Dismutase-1
dc.subject.mesh	Dopaminergic Neurons
dc.subject.mesh	Disease Models, Animal
dc.subject.mesh	Substantia Nigra
dc.subject.mesh	Mice, Transgenic
dc.subject.mesh	Mice
dc.subject.mesh	Humans
dc.subject.mesh	Nerve Degeneration
dc.subject.mesh	Male
dc.subject.mesh	Parkinson Disease
dc.subject.mesh	Female
dc.subject.mesh	Mice, Inbred C57BL
dc.subject.mesh	Copper
dc.subject.mesh	Aged
dc.title	Parkinson-like wild-type superoxide dismutase 1 pathology induces nigral dopamine neuron degeneration in a novel murine model.
dc.type	Journal Article
utslib.citation.volume	149
utslib.location.activity	Germany
utslib.for	1103 Clinical Sciences
utslib.for	1109 Neurosciences
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	2025-04-03T23:11:03Z
pubs.issue	1
pubs.publication-status	Published online
pubs.volume	149
utslib.citation.issue	1

Abstract:

Atypical wild-type superoxide dismutase 1 (SOD1) protein misfolding and deposition occurs specifically within the degenerating substantia nigra pars compacta (SNc) in Parkinson disease. Mechanisms driving the formation of this pathology and relationship with SNc dopamine neuron health are yet to be fully understood. We applied proteomic mass spectrometry and synchrotron-based biometal quantification to post-mortem brain tissues from the SNc of Parkinson disease patients and age-matched controls to uncover key factors underlying the formation of wild-type SOD1 pathology in this disorder. We also engineered two of these factors - brain copper deficiency and upregulated SOD1 protein levels - into a novel mouse strain, termed the SOCK mouse, to verify their involvement in the development of Parkinson-like wild-type SOD1 pathology and their impact on dopamine neuron health. Soluble SOD1 protein in the degenerating Parkinson disease SNc exhibited altered post-translational modifications, which may underlie changes to the enzymatic activity and aggregation of the protein in this region. These include decreased copper binding, dysregulation of physiological glycosylation, and atypical oxidation and glycation of key SOD1 amino acid residues. We demonstrated that the biochemical profile introduced in SOCK mice promotes the same post-translational modifications and the development of Parkinson-like wild-type SOD1 pathology in the midbrain and cortex. This pathology accumulates progressively with age and is accompanied by nigrostriatal degeneration and dysfunction, which occur in the absence of α-synuclein deposition. These mice do not exhibit weight loss nor spinal cord motor neuron degeneration, distinguishing them from transgenic mutant SOD1 mouse models. This study provides the first in vivo evidence that mismetallation and altered post-translational modifications precipitates wild-type SOD1 misfolding, dysfunction, and deposition in the Parkinson disease brain, which may contribute to SNc dopamine neuron degeneration. Our data position this pathology as a novel drug target for this disorder, with a particular focus on therapies capable of correcting alterations to SOD1 post-translational modifications.

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http://hdl.handle.net/10453/186576