Parkinson?s disease (PD) is a progressive, debilitating neurodegenerative disorder with no known cure. While the cause of PD is unknown, oxidative stress, gliosis, excitotoxicity, mitochondrial dysfunction and protein misfolding are all known to play a role in disease pathogenesis. Activation of the Nrf2 pathway is a promising therapeutic approach for PD. Unfortunately, Nrf2-based drugs have relied on electrophilic pharmacophores, which are not tolerated well in patients. A critical barrier to progress in developing more effective Nrf2-based therapies is the current lack of understanding of mechanisms that can safely activate this pathway. Bach1 is a transcription factor that represses Nrf2 gene expression. Our goal is to validate Bach1 inhibition as a novel therapeutic strategy for PD pathogenesis, and to identify new target(s) for intervention. Our central hypothesis is that Bach1 inhibition is neuroprotective in PD due to both Nrf2-dependent and Nrf2-independent mechanisms. This hypothesis is based on the knowledge that genetic deletion and pharmacological inhibition of Bach1 in mice results in constitutive activation of neuroprotective Nrf2-dependent as well as Nrf2-independent genes, and protects against the parkinsonian neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Our objectives are to 1) determine the cell-specific roles of Bach1 in MPTP neurotoxicity in vivo, 2) delineate the role of Bach1 inhibition in mediating ?-synuclein-induced PD, 3) differentiate between Bach1- and Nrf2- dependent pathways in neuroprotection, and 4) identity novel targets for therapeutic intervention. Our expected outcomes include finding that 1) genetic deletion and pharmacological inhibition of Bach1 ameliorates ?-synucleinopathy and MPTP-neurotoxicity in mice; 2) Bach1-mediated neuroprotective mechanisms involve distinct cell types; 3) Bach1 inhibition or deletion protects Nrf2-null mice against MPTP- neurotoxicity; 4) Bach1-dependent mechanisms of neuroprotection involve upregulation of Nrf2-dependent as well as Nrf2-independent neuroprotective genes, whereas Nrf2-dependent antioxidant response element (ARE)-containing genes are critical for Nrf2-dependent mechanisms. Our studies will impact the field by: 1) improving understanding of Bach1 modulation of signaling pathways and downstream neuroprotective events relevant to pre-clinical models of PD; 2) validating a set of novel, non-electrophilic Bach1 inhibitors as potential therapeutic agents for PD and synucleinopathies; and 3) identifying novel targets for therapeutic intervention.
AIM 1 : will test the hypothesis that genetic deletion and pharmacological inhibition of Bach1 protects against different modes of nigrostriatal dopaminergic degeneration.
AIM 2 : will test the hypothesis that Bach1 inhibition attenuates disease development in a mouse model of ?-synucleinopathy.
AIM 3 : will test the hypothesis that Bach1 inhibition confers neuroprotection via Nrf2-dependent and Nrf2-independent mechanisms.
|Ammal Kaidery, Navneet; Thomas, Bobby (2018) Current perspective of mitochondrial biology in Parkinson's disease. Neurochem Int 117:91-113|
|Rane, Anand; Rajagopalan, Subramanian; Ahuja, Manuj et al. (2018) Hsp90 Co-chaperone p23 contributes to dopaminergic mitochondrial stress via stabilization of PHD2: Implications for Parkinson's disease. Neurotoxicology 65:166-173|
|Gaisina, Irina N; Lee, Sue H; Kaidery, Navneet A et al. (2018) Activation of Nrf2 and Hypoxic Adaptive Response Contribute to Neuroprotection Elicited by Phenylhydroxamic Acid Selective HDAC6 Inhibitors. ACS Chem Neurosci 9:894-900|
|Zhu, Xingguo; Xi, Caixia; Thomas, Bobby et al. (2018) Loss of NRF2 function exacerbates the pathophysiology of sickle cell disease in a transgenic mouse model. Blood 131:558-562|
|Tapias, Victor; Jainuddin, Shari; Ahuja, Manuj et al. (2018) Benfotiamine treatment activates the Nrf2/ARE pathway and is neuroprotective in a transgenic mouse model of tauopathy. Hum Mol Genet 27:2874-2892|
|Osipyants, Andrey I; Poloznikov, Andrey A; Smirnova, Natalya A et al. (2018) L-ascorbic acid: A true substrate for HIF prolyl hydroxylase? Biochimie 147:46-54|
|Navneet, Soumya; Cui, Xuezhi; Zhao, Jing et al. (2018) Excess homocysteine upregulates the NRF2-antioxidant pathway in retinal Müller glial cells. Exp Eye Res :|