The goals of our research are to determine the potential for Nrf2 (NF-E2-related factor 2) to be a viable therapeutic target in the treatment of neurodegenerative disease and a potential modulator of neurotoxic insult resulting for exposure to toxic chemicals. Oxidative stress is believed to be a principal factor in the development of many chronic neurodegenerative diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), and amyotrophic lateral sclerosis (ALS), as well as multiple sclerosis (MS). Our 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 in brain. Previously, our laboratory had demonstrated that, in primary mixed cell cultures of cortical neurons and astrocytes, Nrf2 activation in the astrocytes could protect neurons for oxidative stress-induced cell death. To determine if this observation could translate to the in vivo situation, transgenic mice with astrocyte-specific overexpression of Nrf2 (GFAP-Nrf2 mice) were generated. This mouse is more resistant to chemical models of PD and HD, as well as extends lifespan and delays onset of disease in transgenic models of ALS and PD. In addition, we are actively attempting to identify novel Nrf2 activating molecules that cross the blood-brain-barrier and attenuate the progression of neuronal cell death in neurodegenerative disease and following neurotoxic exposure. Identification of multiple new classes of molecules (either synthetic or natural products) that activate the Nrf2 pathway have the potential to impact a wide range of neurological diseases and neurotoxic insults where the Nrf2 pathway has been implicated in being neuroprotective.
Another research project is focused on the role of transthyretin (TTR) as a therapeutic target in the treatment of AD. My laboratory discovered that mice overexpressing mutant forms of amyloid precursor protein (APP) compensate for the increased generation of beta-amyloid (Ab) by upregulating expression and protein levels of TTR. This is in stark contrast to what occurs in human AD patients where TTR levels are reduced compared to age-matched controls. Thus, targeting TTR or at least understanding how TTR can confer protection from Ab toxicity is highly significant. In collaboration with Dr. Regina Murphy, Department of Chemical and Biological Engineering, we have identified the critical regions of TTR responsible for binding and blocking with Ab-mediated neurotoxicity.
Present work is centered on:
- Drug discovery with respect to small molecule activators of the Nrf2-ARE neuroprotective pathway
- Signaling mechanisms responsible for Nrf2-mediated neuroprotection using RNA-Seq, miRNA microarray, and proteomics
- The role of astrocytes in Nrf2-mediated neuroprotection and identification of molecules/proteins released from Nrf2 overexpressing astrocytes
- The role of Nrf2 in microglial activation
- Viral-mediated delivery of Nrf2
- Development of therapeutic approaches using TTR and TTR peptidomimetics in models of AD.
Cho PY, Joshi G, Boersma MD, Johnson JA, Murphy RM (2015). A Cyclic Peptide Mimic of the β-Amyloid Binding Domain on Transthyretin. ACS Chem Neurosci. 6(5):778-89
Joshi G, Gan KA, Johnson DA, Johnson JA (2014). Increased AD-like pathology in the APP/PS1ΔE9 mouse model lacking Nrf2 through modulation of autophagy. Neurobiol Aging, 36(2):664-79.
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