Targeting a Novel Adaptive Stress Response Pathway for Therapeutic Intervention in Alpha-Synuclein-Induced Dementia
Abstract
Parkinson s disease (PD) is the most common movement disorder, characterized by the loss of nigral dopaminergic neurons and the presence of fibrillar cytoplasmic inclusions composed of alpha-synuclein (?S), known as Lewy bodies. Apart from its cardinal motor symptoms, PD is associated with a heterogenous spectrum of non-motor symptoms that contribute significantly to the overall disease burden. Cognitive impairments are one of the essential non-motor manifestations of PD that severely affects the quality of life and has substantial economic consequences. Despite decades of research, there are no existing therapies that can slow or halt the progression of cognitive dysfunction associated with PD, highlighting the urgency to find new therapeutic strategies. The emerging view suggests that the abnormalities in ?S are a strong pathological correlate for motor and neurocognitive dysfunction in PD and Dementia with Lewy Bodies (DLB), a disease clinically and pathologically related to PD. While the mechanism by which ?S pathology leads to neuronal dysfunction is unknown, mounting evidence suggests that compromised redox homeostasis, defects in protein quality control, mitochondrial dysfunction, and neuroinflammation cause ?S aggregation and neurodegeneration in PD and DLB. A promising and validated neurotherapeutic target that could modulate multiple etiological pathways in PD and ?-synucleinopathy involves drug-induced activation of a coordinated genetic program regulated by the transcription factor, nuclear factor E2-related factor 2 (Nrf2). Nrf2 regulates a multifaceted network that integrates cellular activities by expressing cytoprotective genes, promoting the resolution of inflammation, restoring redox and protein homeostasis, stimulating energy metabolism, and facilitating repair. Current strategies to activate the Nrf2 pathway utilize electrophilic pharmacophores that alkylate critical cysteine residues of the Nrf2 inhibitor Kelch-like ECH-associated protein 1 (Keap1), among other proteins important for cellular homeostasis, resulting in side effects, and renders them unusable in PD treatment. An alternate approach is to develop non-electrophilic Nrf2 activators that rely on destabilizing the Keap1-Nrf2 binding non-covalently. Unfortunately, these displacement activators have low potency and exhibit poor blood-brain barrier permeability. As an alternative approach to enhancing Nrf2, we will explore the role of a negative regulator of Nrf2 called Bach1 BTB (broad-complex, tram-track and bric-a-brac) and CNC (cap n collar protein) homology 1. Bach1 is a repressor of Nrf2, a known modulator of ?-synucleinopathy. We propose that inhibiting Bach1 will lead to neuroprotection via activation of Nrf2 and other neuroprotective pathways. Our research is guided by our finding that Bach1 protein levels are significantly upregulated in postmortem PD brains and preclinical models of PD and DLB. Further, genetic deletion and pharmacologic inhibition of Bach1 by a non-electrophilic inhibitor led to constitutive activation of neuroprotective Nrf2-dependent and Nrf2-independent genes to attenuate nigrostriatal dopaminergic neurotoxicity and neurocognitive deficits in preclinical models of PD and dementia. Overlaying of Bach1-bound genes from Bach1 ChIP-seq analysis with differentially expressed gene signatures between human PD dementia and control single-cell RNA-seq data showed that a significant subset of genes driven by Bach1 targets modulate oxidative phosphorylation, iron, and redox homeostasis, autophagy, inflammation, and neurotrophic signaling. These data indicate that Bach1 inhibition may confer therapeutic effects against ?S-mediated cognitive dysfunction and neurodegeneration in PD and DLB by modulating Bach1-targeted pathways. Using state-of-the-art mouse models and novel non-electrophilic Bach1 inhibitors, we propose to delineate a novel mechanistic understanding of how Bach1-targeted neuroprotectiv
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310443
Entities
People
- Bobby Thomas
Organizations
- Medical University of South Carolina
- United States Army