Jeffrey A. Johnson, PhD

Pubmed

More information:

• Dr. Johnson’s School of Pharmacy Home Page

Research Description:

Oxidative stress is likely a principal factor in the development of many chronic neurodegenerative diseases such as Alzheimer’s, Parkinson’s, Huntington’s and Amyotrophic Lateral Sclerosis. Oxidative stress can be defined as an imbalance in which free radicals and their products exceed the capacity of 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 defense mechanisms in the brain by activating multiple antioxidant defense genes simultaneously through activation of the Nrf2-ARE (antioxidant response element) pathway. Transplantation of genetically engineered neural stem cells overexpressing Nrf2 is one approach used to boost this protective pathway.

Additional research involving neural stem cells addresses the role of Nrf2 in neuronal and glial differentiation, differential sensitivity of neurons and astrocytes to oxidative stress-induced cell death, and screening for small molecule activator of the Nrf2-ARE pathway. In our laboratory, we use chemical and genetic models of Parkinson’s disease, Alzheimer’s disease, Huntington’s disease, and Amyotrophic Lateral Sclerosis (Lou Gehrig’s disease).

Selected References:

• Jiwaji Z*, Tiwari SS*, Avilés-Reyes RX*, Hooley M*, Hampton D, Torvell M, Johnson DA, McQueen J, Baxter P, Sabari-Sankar K, Qiu J, He X, Fowler J, Febery J, Gregory J, Rose J, Tulloch J, Loan J, Story D, McDade K, Smith AM, Greer P, Ball M, Kind PC, Matthews PM, Smith C, Dando O, Spires-Jones TL, Johnson JA^#, Chandran S^#, Hardingham GE^#. (2022). Reactive astrocytes acquire neuroprotective as well as deleterious signatures in response to Tau and Aß pathology. Nat Commun. 2022 Jan 10;13(1):135. *Equal contribution and #Corresponding authors.
• Hoang TT, Johnson DA, Raines RT, Johnson JA (2019). Angiogenin activates the astrocytic Nrf2/antioxidant-response element pathway and thereby protects murine neurons from oxidative stress. J Biol Chem. 294(41):15095-15103.
• Joshi G, Gan KA, Johnson DA, Johnson JA (2015).  Increased AD-like pathology in the APP/PS1ΔE9 mouse model lacking Nrf2 through modulation of autophagy. Neurobiol Aging, 36(2):664-79.
• Dowell JA, Johnson DA, Johnson JA (2013).  Mechanisms of Nrf2 Protection in Astrocytes as Identified by Quantitative Proteomics and siRNA Screening.  PLoS One, 8(7):e70163.
• 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.
• Vargas MR., Johnson DA, Johnson JA. (2011). Decreased glutathione accelerates neurological deficit and mitochondrial pathology in familial ALS-linked hSOD1G93A mice model.Neurobiol. Dis. 43(3):543-51.
• 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.