Mutant Cu/Zn-superoxide dismutase associated with amyotrophic lateral sclerosis destabilizes vascular endothelial growth factor mRNA and downregulates its expression.

Mutant Cu/Zn-superoxide dismutase associated with amyotrophic lateral sclerosis destabilizes vascular endothelial growth factor mRNA and downregulates its expression. Research Abstract Details 

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Mutant Cu/Zn-superoxide dismutase associated with amyotrophic lateral sclerosis destabilizes vascular endothelial growth factor mRNA and downregulates its expression. Abstract Text:

Liang Lu,Lei Zheng,Liliana Viera,Esther Suswam,Yanyan Li,Xuelin Li,Alvaro G ,Peter H King,

Vascular endothelial growth factor (VEGF) plays a neuroprotective role in mice harboring mutations of copper-zinc superoxide dismutase 1 (SOD1) in familial amyotrophic lateral sclerosis (ALS). Conversely, the loss of VEGF expression through genetic depletion can give rise to a phenotype resembling ALS independent of SOD1 mutations. Here, we observe a profound downregulation of VEGF mRNA expression in spinal cords of G93A SOD1 mice that occurred early in the course of the disease. Using an in vitro culture model of glial cells expressing mutant SOD1, we demonstrate destabilization and downregulation of VEGF RNA with concomitant loss of protein expression that correlates with level of transgene expression. Using a luciferase reporter assay, we show that this molecular effect is mediated through a portion of the VEGF 3'-untranslated region (UTR) that harbors a class II adenylate/uridylate-rich element. Other mutant forms of SOD1 produced a similar negative effect on luciferase RNA and protein expression. Mobility shift assay with a VEGF 3'-UTR probe reveals an aberrantly migrating complex that contains mutant SOD1. We further show that the RNA stabilizing protein, HuR (human antigen R), is translocated from nucleus to cytoplasm in mutant SOD1 cells in vitro and mouse motor neurons in vivo. In summary, our data suggest that mutant SOD1 gains a novel function, possibly by altering the ribonucleoprotein complex with the VEGF 3'-UTR. We postulate that the resultant dysregulation of VEGF posttranscriptional processing critically reduces the level of this neuroprotective growth factor and accelerates the neurodegenerative process in ALS.

Mutant Cu/Zn-superoxide dismutase associated with amyotrophic lateral sclerosis destabilizes vascular endothelial growth factor mRNA and downregulates its expression. Publishing Authors By Initials

L Lu,L Zheng,L Viera,E Suswam,Y Li,X Li,AG ,PH King,

For similar peptides: intercellular signaling peptides and proteins: angiogenic proteins: vascular endothelial growth factors: vascular endothelial growth factor a research abstracts see: peptides: intercellular signaling peptides and proteins: angiogenic proteins: vascular endothelial growth factors: vascular endothelial growth factor a research

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Mutant Cu/Zn-superoxide dismutase associated with amyotrophic lateral sclerosis destabilizes vascular endothelial growth factor mRNA and downregulates its expression. Journal Published:

PUBLICATION TYPE: Research Support, U.S. Gov't,

Journal: The Journal of neuroscience : the official journal

VOLUME: 27

Page Numbers: 7929-38

Journal Abbreviation: J. Neurosci.

ISSN: 1529-2401

DAY: 25

MONTH: Jul

YEAR: 2007

Mutant Cu/Zn-superoxide dismutase associated with amyotrophic lateral sclerosis destabilizes vascular endothelial growth factor mRNA and downregulates its expression. Information

Number of References:

LANGUAGE: eng

NlmUniqueID: 8102140

Mutant Cu/Zn-superoxide dismutase associated with amyotrophic lateral sclerosis destabilizes vascular endothelial growth factor mRNA and downregulates its expression. Keywords Mesh Terms:

KEYWORDS: Vascular Endothelial Growth Factor A

MESH TERMS: genetics

Chemical & Substance for Abstract: Mutant Cu/Zn-superoxide dismutase associated with amyotrophic lateral sclerosis destabilizes vascular endothelial growth factor mRNA and downregulates its expression. Information

Substance Name: Superoxide Dismutase

Registry Number: EC 1.15.1.1

Grant and Affiliation Information for Mutant Cu/Zn-superoxide dismutase associated with amyotrophic lateral sclerosis destabilizes vascular endothelial growth factor mRNA and downregulates its expression.

AFFILIATION: Department of Neurology, University of Alabama, Birmingham, Birmingham, Alabama 35295, USA.

Country: United States

AGENCY: United States NINDS

GRANT: NS42834

ACRONYM: NS

MEDLINETA: J Neurosci

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