Graduation Year

2023

Document Type

Dissertation

Degree

Ph.D.

Degree Name

Doctor of Philosophy (Ph.D.)

Degree Granting Department

Medical Sciences

Major Professor

David E. Kang, Ph.D.

Committee Member

Vladimir Uversky, Ph.D.

Committee Member

Laura J. Blair, Ph.D.

Committee Member

Lianchun Wang, Ph.D.

Keywords

actin filaments, neurodegeneration, Nrf2, oxidation, SSH1, tauopathy

Abstract

Oxidative damage is one of the earliest events in Alzheimer’s disease (AD) pathogenesis and precedes the clinical stage of disease. The nuclear factor erythroid 2-related factor (Nrf2) is activated in response to oxidative stress, which protects the brain from oxidative damage and AD pathogenesis. Although Nrf2-mediated oxidative stress response declines with age and becomes dysfunctional in AD brains, the mechanistic basis for this dysfunction is unknown. Here, we demonstrate through in vitro and in vivo models, as well as in human AD brain tissue, that Slingshot homolog-1 (SSH1) acts as a counterweight to neuroprotective Nrf2 in response to oxidative stress and disease. This is achieved through oxidative stress-induced activation of SSH1, which sequesters Nrf2 complexes on actin filaments and augments Keap1-Nrf2 interaction, independently of SSH1 phosphatase activity. Human AD brains exhibit excessive inhibitory Nrf2 interactions with SSH1 and Keap1, and elimination of Ssh1 in AD models activates Nrf2, which mitigates tau and Aβ deposition and protects against oxidative injury and neuroinflammation. Loss of Ssh1 also prevents synaptic plasticity impairments and normalizes transcriptomic perturbations in tauP301S mice. These results highlight a previously undescribed mode of Nrf2 blockade through SSH1, which potentially explains oxidative damage and ensuing pathogenesis in AD. Thus, strategies to inhibit SSH1-mediated Nrf2 suppression while preserving SSH1 catalytic function may provide unique therapeutic protection from AD and related disorders.

Download

Included in

Neurosciences Commons

Share

COinS