Jeffrey Johnson, PhD
Position title: Professor, Pharmacy
PhD, University of Wisconsin
School of Pharmacy
University of Wisconsin
777 Highland Ave.
Madison, WI 53705
The Johnson Lab
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 beta2-amyloid. We know, there fore, 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 through activation of the antioxidant response element (ARE). 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: 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 beta2-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 over-expression of amyloid precursor protein on antioxidant gene expression, neuronal survival and plaque formation in Nrf-2 null mice.
Killoy KM, Harlan BA, Pehar M, Helke KL, Johnson JA, Vargas MR. (2018). Decreased glutathione levels cause overt motor neuron degeneration in hSOD1WT over-expressing mice. Experimental Neurology, 302:129-135. doi: 10.1016/j.expneurol.2018.01.004.
Lee LY, Harberg C, Matkowskyj KA, Cook S, Roenneburg D, Werner S, Johnson DA, Johnson JA, Foley DP. (2016) Cell-specific overactivation of nuclear erythroid 2 p45-related factor 2-mediated gene expression in myeloid cells decreases hepatic ischemia/reperfusion injury. Liver Transplantation. 22(8):1115-28. doi: 10.1002/lt.24473.
Joshi G, Gan KA, Johnson DA, Johnson JA. (2015) Increased Alzheimer’s disease-like pathology in the APP/ PS1ΔE9 mouse model lacking Nrf2 through modulation of autophagy. Neurobiology of Aging. 36(2):664-79. doi: 10.1016/j.neurobiolaging.2014.09.004.
Johnson DA, Johnson JA. (2015) Nrf2–a therapeutic target for the treatment of neurodegenerative diseases. Free Radical Biology & Medicine. 88(Pt B):253-67. doi: 10.1016/j.freeradbiomed.2015.07.147.
Cho PY, Joshi G, Boersma MD, Johnson JA, Murphy RM. (2015) A Cyclic Peptide Mimic of the β-Amyloid Binding Domain on Transthyretin. ACS Chemical Neuroscience. 20;6(5):778-89. doi: 10.1021/cn500272a.
Cho PY, Joshi G, Johnson JA, Murphy RM. (2014) Transthyretin-derived peptides as β-amyloid inhibitors. ACS Chemical Neuroscience. ACS Chem Neurosci. 2014 Jul 16;5(7):542-51. doi: 10.1021/cn500014u.
Gan L, Johnson JA. (2014) Oxidative damage and the Nrf2-ARE pathway in neurodegenerative diseases. Biochimica et Biophysica Acta. 1842(8):1208-18. doi: 10.1016/j.bbadis.2013.12.011.
Vargas MR, Burton NC, Kutzke J, Gan L, Johnson DA, Schäfer M, Werner S, Johnson JA. (2013) Absence of Nrf2 or its selective overexpression in neurons and muscle does not affect survival in ALS-linked mutant hSOD1 mouse models. PLoS One. 8(2):e56625.
Gan L, Vargas MR, Johnson DA, Johnson JA. (2012) Astrocyte-specific overexpression of Nrf2 delays motor pathology and synuclein aggregation throughout the CNS in the alpha-synuclein mutant (A53T) mouse model. J Neurosci. 5;32(49):17775-87.
Williamson TP, Johnson DA, Johnson JA. (2012) Activation of the Nrf2-ARE pathway by siRNA knockdown of Keap1 reduces oxidative stress and provides partial protection from MPTP-mediated neurotoxicity. Neurotoxicology. Feb 9;33(3):272-279.
Williamson TP, Amirahmadi S, Joshi G, Kaludov NK, Martinov MN, Johnson DA, Johnson JA. (2012) Discovery of potent, novel Nrf2 inducers via quantum modeling, virtual screening, and in vitro experimental validation. Chemical Biology & Drug Design. Dec;80(6):810-20.