Research

Interest

Molecular mechanisms of neuronal apoptosis, neuronal proliferation and survival, neurodegenerative disorders, trace metal regulation of neuronal p53 and gene expression.

Current Projects

Apoptosis, or programmed cell death is responsible for neuronal death after traumatic brain and spinal cord injury, stroke, and seizures. It also clearly plays a role in many neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS) and Huntington's disease. The Levenson lab is currently exploring the molecular and cellular mechanisms responsible for neuronal proliferation, survival, and apoptosis, with a particular focus on the role of the metals copper, zinc, and iron. Some specific areas of research include:

Zinc: Neuronal Proliferation, Survival, and Apoptosis

Our lab has shown that neuronal proliferation and survival is dependent on proper levels of the trace metal zinc. While we have shown that excess zinc accumulation following traumatic injury can contribute to p53-mediated neuronal damage and death, we have also found that zinc deficiency, which frequently occurs after brain injury, enhances cell death at the site of injury, impairs neuronal proliferation, and impairs repair processes. It is also clear that zinc deficiency regulates a number of important behaviors such as feeding behavior, depression-like behaviors, and anxiety-like behaviors. With a particular focus on the hippocampus and the olfactory bulb where zinc levels are high, we have used cDNA and oligonucleotide microarray to identify a number of important zinc-regulated genes in the CNS that are responsible for the control of neuronal proliferation, repair, survival, and the accompanying behaviors. Recent publications in this area include:

• Levenson, CW and Rich, N. Eat less, live longer? New insights into the role of caloric restriction in the brain. Nutrition Reviews, 65:412-415, 2007.
• Levenson, CW. Zinc: The new antidepressant? Nutrition Reviews 64:39-42, 2006.
• Levenson, CW and Tassabehji, N.M. Role and regulation of copper and zinc transport proteins in the central nervous system. In: Handbook of Neurochemistry and Molecular Neurobiology. Eds. Lajtha, A, and Reith, MEA. 3rd Edition. pp 257-284, 2007.
• Levenson CW. Trace metal regulation of neuronal apoptosis: from genes to behavior. Physiol Behav. 2005 Oct 15;86(3):399-406. Epub 2005 Aug 24. PMID: 16125208 [PubMed - in process] Paper
• Levenson CW. Zinc supplementation: neuroprotective or neurotoxic? Nutr Rev. 2005 Apr;63(4):122-5. Review. PMID: 15869126 [PubMed - indexed for MEDLINE] Paper
• Evans SA, Overton JM, Alshingiti A, Levenson CW. Regulation of metabolic rate and substrate utilization by zinc deficiency. Metabolism. 2004 Jun;53(6):727-32. PMID: 15164319 [PubMed - indexed for MEDLINE] Paper
• Levenson CW. Zinc regulation of food intake: new insights on the role of neuropeptide Y. Nutr Rev. 2003 Jul;61(7):247-9. Review. PMID: 12918877 [PubMed - indexed for MEDLINE] Paper
• Yeiser EC, Vanlandingham JW, Levenson CW. Moderate zinc deficiency increases cell death after brain injury in the rat. Nutr Neurosci. 2002 Oct;5(5):345-52. PMID: 12385597 [PubMed - indexed for MEDLINE] Paper
• VanLandingham JW, Fitch CA, Levenson CW. Zinc inhibits the nuclear translocation of the tumor suppressor protein p53 and protects cultured human neurons from copper-induced neurotoxicity. Neuromolecular Med. 2002;1(3):171-82. PMID: 12095159 [PubMed - indexed for MEDLINE] Paper
• Yeiser EC, Lerant AA, Casto RM, Levenson CW. Free zinc increases at the site of injury after cortical stab wounds in mature but not immature rat brain. Neurosci Lett. 1999 Dec 24;277(2):75-8. PMID: 10624813 [PubMed - indexed for MEDLINE] Paper

Copper: Neuronal Damage and Death in Wilson's Disease

Wilson's disease is characterized by copper accumulation in the liver and brain resulting in damage to nuclear and mitochondrial DNA, hepatic fibrosis and cirrhosis, and neuronal damage. We have shown that one of the key molecular regulators of neuronal proliferation, repair and apoptotic death is the tumor suppressor protein p53. This DNA-binding transcription factor acts on downstream target genes to stop the cell cycle, initiate cellular repair, and, when there is extensive damage, induce the apoptotic cascade to eliminate the cell. Our lab uses a variety of techniques including gene expression profiling of p53 target genes, p53-reponsive reporter genes, and transfection of human neurons with a dominant-negative p53 construct to determine the role of p53 in copper-mediated neuronal damage and death. We have not only identified the molecular cascade responsible for neuronal apoptosis, but have also shown that copper induces a conformational mutant form of p53 with altered transcriptional properties. Recent publications in this area include:

• Blakemore, L., Levenson, CW, Trombley, P.Q. Neuropeptide Y modulates excitatory synaptic transmission in the olfactory bulb. Neuroscience, 138:663-674, 2006.
• Vanlandingham JW, Tassabehji NM, Somers RC, Levenson CW. Expression Profiling of p53-Target Genes in Copper-Mediated Neuronal Apoptosis. Neuromolecular Med. 2005;7(4):311-24. PMID: 16391388 [PubMed - in process] Paper
• Tassabehji NM, VanLandingham JW, Levenson CW. Copper alters the conformation and transcriptional activity of the tumor suppressor protein p53 in human Hep G2 cells. Exp Biol Med (Maywood). 2005 Nov;230(10):699-708. PMID: 16246896 [PubMed - indexed for MEDLINE] Paper
• Levenson CW. Trace metal regulation of neuronal apoptosis: from genes to behavior. Physiol Behav. 2005 Oct 15;86(3):399-406. Epub 2005 Aug 24. PMID: 16125208 [PubMed - in process] Paper
• VanLandingham JW, Fitch CA, Levenson CW. Zinc inhibits the nuclear translocation of the tumor suppressor protein p53 and protects cultured human neurons from copper-induced neurotoxicity. Neuromolecular Med. 2002;1(3):171-82. PMID: 12095159 [PubMed - indexed for MEDLINE] Paper
• Narayanan VS, Fitch CA, Levenson CW. Tumor suppressor protein p53 mRNA and subcellular localization are altered by changes in cellular copper in human Hep G2 cells. J Nutr. 2001 May;131(5):1427-32. PMID: 11340094 [PubMed - indexed for MEDLINE] Paper

Iron: Iron and Parkinson's Disease

The accumulation of iron in the CNS has been linked to a variety of neurodegenerative disorders including Alzheimer's disease, Huntington's disease, and Hallervorden-Spatz syndrome. There is, however, an especially strong association between iron concentrations in the substantia nigra and Parkinson's disease (PD). Recent new work has shown that iron chelation may prevent symptoms of experimentally induced PD. This led us, in collaboration with Mark Mattson at the Laboratory of Neurosciences, National Institute on Aging, to test the possible role of dietary iron restriction on the development of an experimental model of PD using 1-methyl-4-1,2,3,6-tetrahydropyridine (MPTP). In mice that were fed the iron-restricted diet, MPTP did not appear to cause the usual reduction in striatal dopamine production orimpairment of motor behavior. However, when we compared iron-restricted mice to those receiving adequate dietary iron, our data showed that dietary iron deficiency alone resulted in a reduction in striatal dopamine and produced a significant impairment of motor behavior. This may be because iron is a cofactor for tyrosine hydroxylase, the rate-limiting enzyme in dopamine synthesis, and iron deficiency reduces D1 and D2 receptor abundance. Furthermore, our in vitro data using the iron chelator desferrioxamine in both primary cultures of rat neurons and nerve growth factor-treated PC12 cells suggest that iron restriction causes p53-mediated neuronal apoptosis. Our recent publications on the role of iron in the CNS include:

• Levenson CW, Cutler RG, Ladenheim B, Cadet JL, Hare J, Mattson MP. Role of dietary iron restriction in a mouse model of Parkinson's disease. Exp Neurol. 2004 Dec;190(2):506-14. PMID: 15530889 [PubMed - indexed for MEDLINE] Paper
• Levenson CW, Tassabehji NM. Iron and ageing: an introduction to iron regulatory mechanisms. Ageing Res Rev. 2004 Jul;3(3):251-63. Review. PMID: 15231236 [PubMed - indexed for MEDLINE] Paper
• Levenson CW. Iron and Parkinson's disease: chelators to the rescue? Nutr Rev. 2003 Sep;61(9):311-3. Review. PMID: 14552066 [PubMed - indexed for MEDLINE] Paper
• VanLandingham JW, Levenson CW. Effect of retinoic acid on ferritin H expression during brain development and neuronal differentiation. Nutr Neurosci. 2003 Feb;6(1):39-45. PMID: 12608735 [PubMed - indexed for MEDLINE] Paper
• Levenson CW, Fitch CA. Effect of altered thyroid hormone status on rat brain ferritin H and ferritin L mRNA during postnatal development. Brain Res Dev Brain Res. 2000 Jan 3;119(1):105-9. PMID: 10648877 [PubMed - indexed for MEDLINE] Paper