|
|
|
|
|
Johnson, Jeffrey A.
 Jeffrey A. Johnson, PhD
Professor
Research Area: Alzheimer's. Amyotrophic Lateral Sclerosis. Huntington's. Parkinson's. Autoimmune Disease. Molecular mechanism of tert-butylhydroquinone (tBHQ) activation of Antioxidant Response Element-driven genes in neuroblastoma cells, primary neuronal and glial cultures, and in vivo. How ARE-driven genes block cell death. Effect of overexpression of amyloid precursor protein on the ARE and antioxidant genes in neurons and glia.
Home Dept: School of Pharmacy
Affiliated Depts: Molecular and Environmental Toxicology
Address
Pharmaceutical Sciences
6125 Rennebohm Hall
777 Highland Ave
Madison, WI 53705
Phone: 608/262-2893 - Email
Research
The focus of my laboratory is Molecular Neuropharmacology/Neurotoxicology. Oxidative stress is believed to be a principal factor in the development of many chronic neurodegenerative diseases such as Alzheimer's, Parkinson's, Huntington's and Amyotrophic Lateral Sclerosis. In general, oxidative stress can be defined as an imbalance in which free radicals and their products exceed the capacity cellular antioxidant defense mechanisms. A gain in product formation or loss in protective mechanisms can disturb this equilibrium leading to programmed cell death (PCD). PCD occurs normally with the aging process but appears to be accelerated in chronic neurodegenerative diseases due in part to increased oxidative stress. My laboratory's goal is to discover ways to increase the defense mechanisms in brain by activating multiple antioxidant defense genes simultaneously through activation of the antioxidant response element (ARE) - a process we refer to as programmed cell life (PCL). Any increase in the forces that drive PCD therefore must be balanced by increasing the forces driving PCL or the cell will die. Present work in the laboratory is designed to:
1) Identification of novel small molecules that activate the Nrf2-ARE pathway;
2) Characterize the expression pattern and regulation of the ARE in vivo and in primary neuronal and glial cultures derived from ARE transgenic reporter mice;
3) determine the neuroprotective efficacy of transplanted astrocytes and/or neural progenitor cells overexpressing Nrf2;
4) characterize the how changes in glutathione levels effect neurodegeneration; and
5) determine the effect of soluble amyloid precursor protein cleavage products on gene expression and neuronal survival.
The laboratory is actively using chemical and genetic models of Parkinson?s disease, Alzheimer?s disease, Huntington?s disease, Amyotrophic Lateral Sclerosis (Lou Gehrig?s disease), and Epilepsy. The following are links that highlight some of Dr. Johnson's recent findings. http://www.news.wisc.edu/10564.html http://www.news.wisc.edu/10088.html
Publications- Kraft AD, Resch JM, Johnson DA, Johnson JA. Activation of the Nrf2-ARE pathway in muscle and spinal cord during ALS-like pathology in mice expressing mutant SOD1. Exp Neurol. 2007 207(1):107-17.
- Yates MS, Tauchi M, Katsuoka F, Flanders KC, Liby KT, Honda T, Gribble GW,
Johnson DA, Johnson JA, Burton NC, Guilarte TR, Yamamoto M, Sporn MB, Kensler TW. Pharmacodynamic characterization of chemopreventive triterpenoids as exceptionally potent inducers of Nrf2-regulated genes. Mol Cancer Ther. 2007 6(1):154-62. - Onishchenko N, Tamm C, Vahter M, Hokfelt T, Johnson JA, Johnson DA, Ceccatelli S. Developmental exposure to methylmercury alters learning and induces depression-like behavior in male mice. Toxicol Sci. 2007 97(2):428-37.
- Durchdewald M, Beyer TA, Johnson DA, Johnson JA, Werner S, auf dem Keller U. Electrophilic chemicals but not UV irradiation or reactive oxygen species activate Nrf2 in keratinocytes in vitro and in vivo. J Invest Dermatol. 2007 127(3):646-53.
- Kraft AD, Lee JM, Johnson DA, Kan YW, Johnson JA. Neuronal sensitivity to kainic acid is dependent on the Nrf2-mediated actions of the antioxidant response element. J Neurochem. 2006 98(6):1852-65.
- Kraft, A.D., Lee, J.M., Johnson, D.A., Kan Y.W. and J.A. Johnson (2006). Nrf2-mediated actions of the antioxidant response element are essential for the cellular damage response to kainic acid. J. Neurochem. 98(6):1852-65.
- Lee, J.M., Li, J., Johnson,, D.A., Stein, T.D., Kraft, A.D., Calkins, M.J., Jakel, R. and J.A. Johnson (2005). Nrf2, a Multi-organ Protector? FASEB J. 19(9):1061-6.
- Li, J., Spletter, M.L. and J.A. Johnson (2005). Dissecting tBHQ induced ARE driven gene expression through long and short oligonucleotide arrays. Physiol. Genomics 21(1):43-58.
- Calkins, M.J., Jakel, R.J., Johnson, D.A., Chan K., Kan Y.W. and J.A. Johnson (2005). Protection from mitochondrial complex II inhibition in vitro and in vivo by Nrf2-mediated transcription. Proc. Natl.Acad. Sci. USA. 102(1):244-9.
- Li, J., Johnson,, D.A., Calkins, M.J., Wright, L.S., Svendsen, C.N. and J.A. Johnson (2004). Stabilization of Nrf2 by tBHQ Confers Protection Against Oxidative Stress-induced Cell Death in Human Neural Stem Cells. Toxicol. Sci. 83(2):313-28.
- Stein, T.D., Anders, N.J., DeCarli, C., Chan, S.L., Mattson, M.P. and J.A. Johnson (2004). Neutralization of transthyretin reverses the neuroprotective effects of sAPPalpha in APPSw mice resulting in tau phosphorylation and loss of hippocampal neurons: support for the amyloid hypothesis. J. Neurosci. 24(35):7707-17.
- Li, J., Stein, T.D. and J.A. Johnson (2004). Genetic Dissection of Systemic Autoimmune Disease in Nrf2 Deficient Mice. Physiol. Genomics 18(3):261-72.
- Lee, J.M., Chan, K., Kan, Y.W. and J.A. Johnson (2004). Targeted Disruption of Nrf2 Causes Regenerative Immune-Mediated Hemolytic Anemia. Proc. Natl. Acad. Sci. USA 101(26):9751-6.
- Kraft, A.D., Johnson, D.A. and J.A. Johnson (2004). Nrf2-dependent ARE activation by tBHQ and sulforaphane occurring preferentially in astrocytes conditions neurons against oxidative insult. J. Neurosci. 24: 1101-1112.
- Lee, J.M., Shih, A.Y., Murphy, T.H. and J.A. Johnson (2003). NF-E2- related factor 2 mediates neuroprotection against mitochondrial complex I inhibitors and increased concentrations of intracellular calcium in primary cortical neurons. J. Biol. Chem. 278 (39): 37948-56.
- Lee, J.M., Calkins, M.J., Chan, K., Kan, Y.W. and J.A. Johnson (2003). Identification of the NF-E2-related factor 2-dependent genes conferring protection against oxidative stress in primary cortical astrocytes using oligonucleotide microarray analysis. J Biol. Chem. 278:12029-38.
- Stein, T.D. and J.A. Johnson (2002). Lack of neurodegeneration in transgenic mice overexpressing mutant amyloid precursor protein is associated with increased levels of transthyretin and activation of cell survival pathways. J. Neurosci. 22: 7380-7388.
- Johnson, D.A., Xu, W., Andrews, G.A. and J.A. Johnson (2002). Activation of the antioxidant response element in primary cortical neuronal cultures derived from transgenic reporter mice. J. Neurochem. 81(6):1233-1241.
Check PubMed for other publications by Jeffrey A. Johnson
|
|
|
|
