The focus of the laboratory is Molecular Neuropharmacology/Neurodegeneration.  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.  The laboratories goal is to discover ways to increase the defense mechanisms in brain by activating multiple antioxidant defense genes simultaneously through activation of the Nrf2-ARE pathway.  Present work in the laboratory is focused on: 1) drug discovery with respect to small molecule activators of the Nrf2-ARE neuroprotective pathway; 2) signaling mechanisms responsible for Nrf2-mediated neuroprotection using proteomics; 3) role of astrocytes in Nrf2-mediated neuroprotection; 4) the role of Nrf2 in microglial activation; and 5) viral-mediated delivery of Nrf2 and/or transplantation of Nrf2 overexpressing progenitor cells into animal models of Alzheimer’s Disease, ALS, Huntington’s Disease and Parkinson’s Disease.

Faculty Director of the Bachelor of Science, Pharmacology-Toxicology Program

Background: Dr. Johnson received a BS in Biology (1984) and MS in Pharmacology (1986) from the University of Minnesota-Duluth, and a PhD in Environmental Toxicology (1992) from the University of Wisconsin. He did postdoctoral training in the Department of Pharmacology at the University of Washington and spent four years as an assistant professor at the University of Kansas Medical Center before joining the University of Wisconsin School of Pharmacy faculty in 1999. Dr. Johnson is the Director of the Pharmacology and Toxicology BS program. He is also a member of the Waisman Center, Center for Neuroscience, Neuroscience Training Program, Cellular and Molecular Biology Training Program, MD/PhD Training Program, Molecular and Environmental Toxicology Training Program, and Molecular and Cellular Pharmacology Training Program.

Professional Interests: Transcriptional control of neuroprotective genes and prevention of neurodegeneration in Parkinson's, Alzheimer's, Huntington's and neuromuscular disease.  A focus on dysfunctional proteostasis in disease progression and viral-mediated delivery of protective genes to the brain.

Education:

• BS 1984 Biology - University of Minnesota-Duluth
• MS 1986 Pharmacology - University of Minnesota-Duluth
• PhD 1992 Environ. Toxicology - University of Wisconsin
• Postdoctoral 1995 Neuroscience - University of Washington

Selected from a total of 82 publications.

• Yang DT, Joshi G, Cho PY, Johnson JA, Murphy RM (2013).  Transthyretin as both Sensor and Scavenger of Abeta Oligomers. Biochemistry, 52(17):2849-61.
• Fischedick JT, StandifordM, Johnson DA, Johnson JA (2013).  Structure activity relationship of phenolic diterpenes from Salvia officinalis as activators of the nuclear factor E2-related factor 2 pathway.  Bioorg Med Chem. 21(9):2618-22.
• Vargas MR, Burton NC, Johnson DA, Schäfer M, Werner S, Messing A, Johnson JA (2013).  Absence of Nrf2 or its selective over-expression in neuronal and muscle cells does not affect survival in ALS-linked mutant hSOD1 mouse models.  PLoS One 8(2):e56625.
• Zhang L, Johnson DA, Johnson JA (2013). Deletion of Nrf2 impairs functional recovery, reduces clearance of myelin debris and decreases axonal remyelination after peripheral nerve injury.  Neurobiol Dis. 54:329-38.
• 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. 32(49): 17775-17787.
• 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 and Drug Design, 80(6):810-20.
• 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, 33(3):272-9.
• Vargas MR., Johnson DA, Johnson JA. (2011).  Decreased glutathione accelerates neurological deficit and mitochondrial pathology in familial ALS-linked hSOD1^G93A mice model.  Neurobiol. Dis. 43(3):543-51.
• Calkins M, Townsend JA, Johnson DA, Johnson JA. (2010).  Cystamine Protects from 3-Nitropropionic Acid Lesioning via Induction of NF-E2 Related Factor 2 Mediated Transcription. Exp Neurol. 224(1):307-17.
• Calkins M, Vargas MR, Johnson DA, Johnson JA. (2010).  Astrocyte specific overexpression of Nrf2 protects striatial neurons from mitochondrial complex II inhibition.  Toxicol Sci. 115(2):557-68.
• Gan L, Johnson DA, Johnson JA. (2010). Keap1-Nrf2 Activation in the Presence and Absence of DJ-1.  Eur. J. Neurosci., M 31(6):967-77.  (ES10042-8)
• Johnson DA, Amirahmadi S, Ward C, Fabry Z, Johnson JA. (2010).  The Absence of the Pro-Antioxidant Transcription Factor Nrf2 Exacerbates Experimental Autoimmune Encephalomyelitis.  Toxicol. Sci. 114(2), 237–246.
• 62) Liu L, Hou J, Du J, Chumanov RS, Xu Q, Ge Y, Johnson JA, Murphy RM. (2009). Differential modification of Cys10 alters transthyretin's effect on beta-amyloid aggregation and toxicity.  Protein Eng Des Sel. 22(8):479-88.
• Dowell JA, Johnson JA, Li L. (2009). Identification of Astrocyte Secreted Proteins with a Combination of Shotgun Proteomics and Bioinformatics.  J Proteome Res. 8(8):4135-43.
• Chen PC, Vargas MR, Pani AK, Smeyne RJ, Johnson DA, Kan YW, 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(8):2933-8.
• Vargas, M.R., Johnson, D.A., Sirkis, D.W., Messing, A. and J.A. Johnson  (2008). Nrf2 activation in astrocytes protects against neurodegeneration in mouse models of familial amyotrophic lateral sclerosis. J. Neurosci. 28(50):13574-81.
• Kraft, A.D., Resch, J.M., Johnson, D.A. 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(1):107-17.
• 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.
• 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., Spletter, M.L., Johnson, D.A., Wright,  L.S.,  Svendsen, C.N. and J.A. Johnson (2004).  Rotenone induced caspase 9/3 independent and dependent cell death in undifferentiated and differentiated human neural stem cells. J. Neurochem. 92(3):462-76.
• 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 APP_Sw mice resulting in tau phosphorylation and loss of hippocampal neurons: support for the amyloid hypothesis. J. Neurosci. 24(35):7707-17.
• 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.