Environmental toxins, therapeutic agents, and even endogenous neurotransmitters can produce degeneration and cell death in the nervous system. In many cases, neuronal death caused by neurotoxic agents resembles the naturally occurring cell death that accompanies nervous system development. The goal of our research is to understand the molecular mechanisms that underlie neuronal death and neuronal survival.

As a model system, we study a type of cell death called apoptosis that occurs when neurons are deprived of survival promoting molecules called neurotrophic factors or when neurons are exposed to certain toxic agents. Because this type of cell death requires ongoing RNA and protein synthesis, we have hypothesized that genes specifically expressed during neuronal death are likely to be important components of the cell death program. Consistent with this hypothesis, we have identified several genes that increase in expression during programmed cell death (PCD). Presently, we are testing specific pharmacological and molecular inhibitors of the proteins encoded by these genes for their effects on neuronal survival. Ultimately, we hope to determine how these proteins are activated during cell death and how they, in turn, activate downstream events in the cell death program.

A second area of interest involves the identification of the signal transduction events critical for neuronal survival. Using biochemical and molecular biology techniques, we are testing specific signaling molecules for their ability to promote neurotrophic factor-independent cell survival. Recently, we have demonstrated requirements for phosphatidylinositol 3-kinase and NF-kB activation in the survival of neurons. By examining the downstream targets of these proteins, we hope to identify the critical regulators of neuronal survival.

Role of SM-20 in neuronal cell death. Expression of SM-20 is upregulated during neuronal apoptosis and its overexpression in neurons causes cell death. Liz Lipscomb, a Toxicology graduate student, found that SM-20 is a mitochondrial protein that induces cell death through activation of cysteine proteases called caspases. SM-20 could function as an indirect activator of downstream (1) or upstream (2) caspases. Alternatively, it may be released from mitochondria into the cytosol during cell death (3) to function as a caspase activator.

Recent Publications

Barone MC, Desouza LA, Freeman RS. Pin1 promotes cell death in NGF-dependent neurons through a mechanism requiring c-Jun activity. J Neurochem. 2008 May 9. [Epub ahead of print]

Lomb DJ, Straub JA, Freeman RS. Prolyl hydroxylase inhibitors delay neuronal cell death caused by trophic factor deprivation. J Neurochem. 2007 Dec;103(5):1897-1906

Fu J, Menzies K, Freeman RS, Taubman MB. EGLN3 prolyl hydroxylase regulates skeletal muscle differentiation and myogenin protein stability. J Biol Chem. 2007 Apr 27;282(17):12410-12418.

Brookes PS, Freeman RS, Barone MC. 2006. A shortcut to mitochondrial signaling and pathology: A commentary on “Nonenzymatic formation of succinate in mitochondria under oxidative stress”. Free Radic Biol Med. Jul 1;41(1):41-45.

Clifton DR, Rydkina E, Huyck H, Pryhuber G, Freeman RS, Silverman DJ, Sahni SK. 2005. Expression and secretion of chemotactic cytokines IL-8 and MCP-1 by human endothelial cells after Rickettsia rickettsii infection: regulation by nuclear transcription factor NF-kappaB. Int J Med Microbiol. Aug;295(4):267-278.

Lee S, Nakamura E, Yang H, Wei W, Linggi MS, Sajan MP, Farese RV, Freeman RS, Carter BD, Kaelin WG Jr, Schlisio S. 2005. Neuronal apoptosis linked to EglN3 prolyl hydroxylase and familial pheochromocytoma genes: developmental culling and cancer. Cancer Cell. Aug;8(2):155-167.

Xie L, Johnson RS, Freeman RS. 2005. Inhibition of NGF deprivation-induced death by low oxygen involves suppression of BIMEL and activation of HIF-1. J Cell Biol. Mar 14;168(6):911-920.

Freeman RS, Barone MC. 2005. Targeting hypoxia-inducible factor (HIF) as a therapeutic strategy for CNS disorders. Curr Drug Targets CNS Neurol Disord. Feb;4(1):85-92. Review.

Clifton DR, Rydkina E, Freeman RS, and Sahni SK. 2005. NF-kappaB activation during Rickettsia rickettsii infection of endothelial cells involves the activation of catalytic IkappaB kinases IKKalpha and IKKbeta and phosphorylation-proteolysis of the inhibitor protein IkappaBalpha. Infect Immun. Jan;73(1):155-165.

Freeman RS, Burch RL, Crowder RJ, Lomb DJ, Schoell MC, Straub JA, and Xie L. 2004. NGF deprivation-induced gene expression: after ten years, where do we stand? Prog Brain Res. 146:111-126. Review.