Jeffrey A. Johnson

Signal Transduction, Neurotoxicity, and Transcriptional Control of Neuroprotective Genes

Research Strengths: Molecular Neuroscience, Neurobiology of Disease

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 by the pathology of Alzheimer's Disease, presumably due to increased oxidative stress caused by ß-amyloid. We know, therefore, the driving force for the development of Alzheimer's Disease; however, we have little knowledge of how the different genes and proteins contributing to antioxidant defenses are regulated in brain. My laboratories goal is to discover ways to increase the defense mechanisms in brain by activating multiple antioxidant defense genes simultaneously. A process we refer to a 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 determine: 1) Determine the molecular mechanism(s) by which tert-butyl hydroquinone (tBHQ) activates the ARE; 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 if ARE activation can block apoptosis induced by oxidative stress and beta-amyloid; 4) identify and understand the regulation of ARE-driven genes in mouse and human primary neuronal and glial cultures through the use of Affymetrix oligonucleotide microarrays; 5) characterize the role of Nrf2 in regulation of ARE activation and PCL in the brains of Nrf2 null mice; and 6) determine the effect of overexpression of amyloid precursor protein on antioxidant gene expression, neuronal survival and plaque formation in Nrf-2 null mice. In addition to the Alzheimer's mice, we are presently studying transgenic animal models for Amyotrophic Lateral Sclerosis, Parkinson's Disease and Huntington's Disease.

Nrf2 Overexpression Protects Neurons	Increasing TTR and IGF-2 Block Ab-induced Neurodegeneration

Selected Publications:

Chen, P.C., M.R. Vargas, A.K. Pani, R.J. Smeyne, D.A. Johnson, Y.W. Kan, and J.A. Johnson. 2009. Nrf2-mediated neuroprotection in the MPTP mouse model of Parkinson's disease: Critical role for the astrocyte. Proc. Natl. Acad. Sci. U. S. A. 106:2933-8. [PDF]
Vargas, M.R., D.A. Johnson, D.W. Sirkis, A. Messing, and J.A. Johnson. 2008. Nrf2 activation in astrocytes protects against neurodegeneration in mouse models of familial amyotrophic lateral sclerosis. J. Neurosci. 28:13574-81. [PDF]
Kraft, A.D., J.M. Resch, D.A. Johnson, and J.A. Johnson. 2007. Activation of the Nrf2-ARE pathway in muscle and spinal cord during ALS-like pathology in mice expressing mutant SOD1. Exp. Neurol. 207:107-17. [PDF]
Kraft, A.D., J.M. Lee, D.A. Johnson, Y.W. Kan, 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. 98:1852-65.
Lee, J.M., J. Li, D.A. Johnson, T.D. Stein, A.D. Kraft, M.J. Calkins, R. Jakel, and J.A. Johnson. 2005. Nrf2, a multi-organ protector? FASEB J. 19: 1061-1066.
Calkins, M.J., R.J. Jakel, D.A. Johnson, K. Chan, Y.W. Kan, and J.A. Johnson. 2005. Protection from mitochondrial complex II inhibition in vitro and in vivo by Nrf2-mediated transcription. Proc. Natl. Acad. Sci. U.S.A. 102: 244-249. [PDF]
Jakel, R.J., J.T. Kern, D.A. Johnson, and J.A. Johnson. 2005. Induction of the protective antioxidant response element pathway by 6-hydroxydopamine in vivo and in vitro. Toxicol. Sci. 87: 176-186. [PDF]
Li, J., M.L. Spletter, D.A. Johnson, L.S. Wright, C.N. Svendsen, and J.A. Johnson. 2005. Rotenone induced caspase 9/3 independent and dependent cell death in undifferentiated and differentiated human neural stem cells. J. Neurochem. 92: 462-476. [PDF]
Stein, T.D., N.J. Anders, C. DeCarli, S.L. Chan, M.P. Mattson, 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: 7707-7717. [PDF]
Kraft, A.D., D.A. Johnson, 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. [PDF]
Lee, J.M., A.Y. Shih, T.H. Murphy, 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 :37948-37956. [PDF]
Stein, T.D. and J.A. Johnson. 2003. Genetic programming by the proteolytic fragments of the amyloid precursor protein: Somewhere between confusion and clarity. Rev. Neurosci. 14:317-341.
Wright, L.S., J. Li, M.A.Caldwell, K. Wallace, J.A. Johnson, and C.N. Svendsen. 2003. Gene expression in human neural stem cells: effects of leukemia inhibitory factor. J. Neurochem. 86: 179-95. [PDF]
Shih, A.Y., D.A. Johnson, G. Wong, A.D. Kraft, L. Jiang, H. Erb, J.A. Johnson, and T.H. Murphy. 2003. Coordinate regulation of glutathione biosynthesis and release by Nrf2 expressing glia potently protects neurons from oxidative stress. J. Neurosci. 23: 3394-3406. [PDF]
Lee, J.M., M.J. Calkins, K. Chan, Y.W. Kan, 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: 12029-12038. [PDF]
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. [PDF]
Johnson, D.A., W. Xu, G.A. Andrews, and J.A. Johnson. 2002. Activation of the antioxidant response element in primary cortical neuronal cultures derived from transgenic reporter mice. J. Neurochem. 81: 1233-1241. [PDF]
Li, J. and J. A. Johnson. 2002 Time-dependent changes in antioxidant responsive element (ARE)-driven gene expression through use of a simple noise-filtering process for microarray data. Physiol. Genomics 9: 137-144. [PDF]
Li, J., G.A. Lee, and J.A. Johnson. 2002. Microarray analysis reveals an antioxidant responsive element-driven gene set involved in conferring protection from oxidative stress-induced apoptosis in IMR-32 cells. J. Biol. Chem. 277: 388-394. [PDF]