Amyotrophic lateral sclerosis (ALS) is a devastating disease. Recent evidence indicates that vascular endothelial growth factor (VEGF) is a critical element for neuroprotection during cellular stress, and that its down-regulation in neural tissues contributes to accelerated motor neuron death. One molecular pathway that promotes VEGF up-regulation in response to cellular stress is RNA stabilization. When cells are exposed to stress, such as hypoxic exposure, oxidative metabolites, or inflammatory cytokine exposure, however, the VEGF transcript becomes stabilized, resulting in enhanced expression and subsequent neuroprotection. In our preliminary studies with the superoxide dismutase (SOD1) mutant mouse model of ALS, we have observed a marked diminution of VEGF mRNA levels that is linked to VEGF RNA destabilization. In this proposal, we will test two closely related hypotheses: 1) VEGF destabilization and down-regulation is due to dysfunction of the RNA stabilizer, HuR, in the presence of mutant SOD1. 2) Intercellular signaling between astrocytes and neurons triggers the aberrant VEGF mRNA stabilization response.
Three specific aims are proposed to test these hypotheses. First, we will investigate the role of cytoplasmic HuR translocation and mutant SOD1 in the destabilization and down-regulation of VEGF mRNA. Second, we will analyze the interaction between mutant SOD1 proteins, HuR and the RNP complex associated with the VEGF 3'UTR to determine why mutant SOD1 negatively affects VEGF RNA processing. Third, we will investigate the impact of the mutant SOD1-induced VEGF destabilization in a co-culture model of motor neuron-like cells and glial cells that express wild-type or mutant SOD1. Relevance: This proposal has the promise to elucidate the mechanism by which VEGF is down regulated in mutant SOD1 mice, and to provide a possible molecular link between two important aspects of ALS pathology: VEGF and SOD1 mutant proteins. Further investigation of this link could provide insight into the pathogenesis of ALS, and ultimately therapeutic intervention for this currently incurable disorder.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Clinical Investigator Award (CIA) (K08)
Project #
Application #
Study Section
NST-2 Subcommittee (NST)
Program Officer
Sutherland, Margaret L
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Alabama Birmingham
Schools of Medicine
United States
Zip Code
Si, Ying; Cui, Xianqin; Kim, Soojin et al. (2014) Smads as muscle biomarkers in amyotrophic lateral sclerosis. Ann Clin Transl Neurol 1:778-87
Lu, Liang; Zheng, Lei; Si, Ying et al. (2014) Hu antigen R (HuR) is a positive regulator of the RNA-binding proteins TDP-43 and FUS/TLS: implications for amyotrophic lateral sclerosis. J Biol Chem 289:31792-804
Suswam, Esther A; Shacka, John J; Walker, Kiera et al. (2013) Mutant tristetraprolin: a potent inhibitor of malignant glioma cell growth. J Neurooncol 113:195-205
Kazamel, Mohamed; Cutter, Gary; Claussen, Gwendolyn et al. (2013) Epidemiological features of amyotrophic lateral sclerosis in a large clinic-based African American population. Amyotroph Lateral Scler Frontotemporal Degener 14:334-7
Li, Xuelin; Lin, Wei-Jye; Chen, Ching-Yi et al. (2012) KSRP: a checkpoint for inflammatory cytokine production in astrocytes. Glia 60:1773-84
Oh, Shin J; Morgan, Marla B; Lu, Liang et al. (2009) Racial differences in myasthenia gravis in Alabama. Muscle Nerve 39:328-32
Li, Xuelin; Lu, Liang; Bush, Donald J et al. (2009) Mutant copper-zinc superoxide dismutase associated with amyotrophic lateral sclerosis binds to adenine/uridine-rich stability elements in the vascular endothelial growth factor 3'-untranslated region. J Neurochem 108:1032-44
Lu, Liang; Wang, Shuying; Zheng, Lei et al. (2009) Amyotrophic lateral sclerosis-linked mutant SOD1 sequesters Hu antigen R (HuR) and TIA-1-related protein (TIAR): implications for impaired post-transcriptional regulation of vascular endothelial growth factor. J Biol Chem 284:33989-98
Oh, Shin J; Dhall, Rohit; Young, Angela et al. (2008) Statins may aggravate myasthenia gravis. Muscle Nerve 38:1101-7