QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

HOME  |   SEARCH  |   ARCHIVE  |   SUBSCRIBE  |   CONTACT  |   HELP

The Journal of Neuroscience, July 25, 2007, 27(30):7929-7938; doi:10.1523/JNEUROSCI.1877-07.2007

This Article Full Text Full Text (PDF) Supplemental Data Submit an eLetter Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (1) Citing Articles via Google Scholar Google Scholar Articles by Lu, L. Articles by King, P. H. Search for Related Content PubMed PubMed Citation Articles by Lu, L. Articles by King, P. H. Pubmed/NCBI databases Gene GEO Profiles HomoloGene UniGene Substance via MeSH Medline Plus Health Information Amyotrophic Lateral Sclerosis Genetics Home Reference

 Previous Article  |  Next Article 

Neurobiology of Disease
Mutant Cu/Zn-Superoxide Dismutase Associated with Amyotrophic Lateral Sclerosis Destabilizes Vascular Endothelial Growth Factor mRNA and Downregulates Its Expression

Liang Lu,^1,4 Lei Zheng,¹ Liliana Viera,⁵ Esther Suswam,¹ Yanyan Li,^1,4 Xuelin Li,^1,4 Alvaro G. Estévez,^5,6 and Peter H. King^1,2,3,4

Departments of ¹Neurology, ²Genetics, and ³Physiology and Biophysics, University of Alabama, Birmingham, and ⁴Birmingham Veterans Affairs Medical Center, Birmingham, Alabama 35295, and ⁵Laboratory of Motor Neuron Biology, Burke Medical Research Institute, ⁶Department of Neurology and Neurosciences, Weill Medical College of Cornell University, White Plains, New York 10605

Correspondence should be addressed to Dr. Peter H. King, 1530 Third Avenue South, Birmingham, AL 35294-0017. Email: pking{at}uab.edu

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.

Key words: AU-rich element; 3'-untranslated region; RNA-binding proteins; posttranscriptional gene regulation; HuR translocation; motor neurons

---

Received Jan. 24, 2007; revised May 25, 2007; accepted June 13, 2007.

Correspondence should be addressed to Dr. Peter H. King, 1530 Third Avenue South, Birmingham, AL 35294-0017. Email: pking{at}uab.edu

This article has been cited by other articles:

				F. Farooq, S. Balabanian, X. Liu, M. Holcik, and A. MacKenzie p38 Mitogen-activated protein kinase stabilizes SMN mRNA through RNA binding protein HuR Hum. Mol. Genet., November 1, 2009; 18(21): 4035 - 4045. [Abstract] [Full Text] [PDF]

				C. Ruiz de Almodovar, D. Lambrechts, M. Mazzone, and P. Carmeliet Role and Therapeutic Potential of VEGF in the Nervous System Physiol Rev, April 1, 2009; 89(2): 607 - 648. [Abstract] [Full Text] [PDF]

Home  |   Search  |   Archive  |   Subscribe  |   Contact  |   Help