A Proposed Mechanism for Neurodegeneration in Movement Disorders Characterized by Metal Dyshomeostasis and Oxidative Stress

Trist, BG; Hare, DJ; Double, KL

A Proposed Mechanism for Neurodegeneration in Movement Disorders Characterized by Metal Dyshomeostasis and Oxidative Stress

Trist, BG Hare, DJ

Double, KL

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Publication Type:: Journal Article
Citation:: Cell Chemical Biology, 2018, 25 (7), pp. 807 - 816
Issue Date:: 2018-07-19

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Field	Value	Language
dc.contributor.author	Trist, BG	en_US
dc.contributor.author	Hare, DJ https://orcid.org/0000-0002-5922-7643	en_US
dc.contributor.author	Double, KL	en_US
dc.date.available	2018-05-01	en_US
dc.date.issued	2018-07-19	en_US
dc.identifier.citation	Cell Chemical Biology, 2018, 25 (7), pp. 807 - 816	en_US
dc.identifier.issn	2451-9456	en_US
dc.identifier.uri	http://hdl.handle.net/10453/128165
dc.description.abstract	© 2018 Elsevier Ltd Shared molecular pathologies between distinct neurodegenerative disorders offer unique opportunities to identify common mechanisms of neuron death, and apply lessons learned from one disease to another. Neurotoxic superoxide dismutase 1 (SOD1) proteinopathy in SOD1-associated familial amyotrophic lateral sclerosis (fALS) is recapitulated in idiopathic Parkinson disease (PD), suggesting that these two phenotypically distinct disorders share an etiological pathway, and tractable therapeutic target(s). Despite 25 years of research, the molecular determinants underlying SOD1 misfolding and toxicity in fALS remain poorly understood. The absence of SOD1 mutations in PD highlights mounting evidence that SOD1 mutations are not the sole cause of SOD1 protein misfolding occasioning oligomerization and toxicity, reinforcing the importance of non-genetic factors, including protein metallation and post-translational modification in determining SOD1 stability and function. We propose that these non-genetic factors underlie the misfolding and dysfunction of SOD1 and other proteins in both PD and fALS, constituting a shared and tractable pathway to neurodegeneration. Trist et al. propose a shared etiological pathway in Parkinson disease and SOD1-associated familial amyotrophic lateral sclerosis, whereby concomitant changes in cellular copper and oxidative stress within dying neurons contribute to the dysfunction of specific proteins that are essential for maintaining neuronal health, including superoxide dismutase 1.	en_US
dc.relation.ispartof	Cell Chemical Biology	en_US
dc.relation.isbasedon	10.1016/j.chembiol.2018.05.004	en_US
dc.subject.mesh	Animals	en_US
dc.subject.mesh	Humans	en_US
dc.subject.mesh	Movement Disorders	en_US
dc.subject.mesh	Metals	en_US
dc.subject.mesh	Oxidative Stress	en_US
dc.subject.mesh	Homeostasis	en_US
dc.subject.mesh	Mutation	en_US
dc.subject.mesh	Superoxide Dismutase-1	en_US
dc.title	A Proposed Mechanism for Neurodegeneration in Movement Disorders Characterized by Metal Dyshomeostasis and Oxidative Stress	en_US
dc.type	Journal Article
utslib.citation.volume	7	en_US
utslib.citation.volume	25	en_US
utslib.for	0601 Biochemistry and Cell Biology	en_US
pubs.embargo.period	Not known	en_US
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	closed_access
pubs.issue	7	en_US
pubs.publication-status	Published	en_US
pubs.volume	25	en_US

Abstract:

© 2018 Elsevier Ltd Shared molecular pathologies between distinct neurodegenerative disorders offer unique opportunities to identify common mechanisms of neuron death, and apply lessons learned from one disease to another. Neurotoxic superoxide dismutase 1 (SOD1) proteinopathy in SOD1-associated familial amyotrophic lateral sclerosis (fALS) is recapitulated in idiopathic Parkinson disease (PD), suggesting that these two phenotypically distinct disorders share an etiological pathway, and tractable therapeutic target(s). Despite 25 years of research, the molecular determinants underlying SOD1 misfolding and toxicity in fALS remain poorly understood. The absence of SOD1 mutations in PD highlights mounting evidence that SOD1 mutations are not the sole cause of SOD1 protein misfolding occasioning oligomerization and toxicity, reinforcing the importance of non-genetic factors, including protein metallation and post-translational modification in determining SOD1 stability and function. We propose that these non-genetic factors underlie the misfolding and dysfunction of SOD1 and other proteins in both PD and fALS, constituting a shared and tractable pathway to neurodegeneration. Trist et al. propose a shared etiological pathway in Parkinson disease and SOD1-associated familial amyotrophic lateral sclerosis, whereby concomitant changes in cellular copper and oxidative stress within dying neurons contribute to the dysfunction of specific proteins that are essential for maintaining neuronal health, including superoxide dismutase 1.

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http://hdl.handle.net/10453/128165