Friday, May 9, 2025
5/9/2025
SSH1-Nrf2 nexus in tipping the balance between degeneration and protection in tauopathies. - Project Summary Accumulating evidence indicates that the ability to mount an effective Nrf2-mediated gene expression response to oxidative stress declines during the aging process. In particular, nuclear but not cytoplasmic Nrf2 is depleted in neurons of AD patients. In animal models, loss of Nrf2 signaling exacerbates amyloid and tau deposition, neuroinflammation, and cognitive deficits, whereas induction of Nrf2 signaling protects against these phenotypes. While toxic tau assemblies, oxidative stress, cytoskeletal disruption, and autophagy defects are cardinal features of tauopathies, including AD, how these cellular brain phenotypes integrate at the molecular level to produce physiological or pathological responses during tau pathogenesis is unknown. In addition to the known regulation of the cytoskeleton, mitochondria, and autophagy by SSH1, our new preliminary studies show that the SSH1 pathway intersects with the Nrf2 to inhibit and titrate Nrf2 signaling. Our overarching hypothesis is that the nexus between the SSH1 and Nrf2 pathways represents a tipping point that tips the balance between degeneration and protection during proteotoxic and oxidative stress in tauopathies. As both Nrf2 and SSH1 are activated under oxidative stress, understanding how the nexus between Nrf2 and SSH1 is physiologically and pathologically regulated will provide key insights into treating AD and other tauopathies. Utilizing in vitro recombinant proteins, cellular models, animal models, and postmortem brains combined with mechanistic biochemical, immunochemical, in situ proximity ligation assays, RNA- seq, and proteomics studies, we will define and dissect how the SSH1-Nrf2 nexus tips the balance between neurodegeneration vs. neuroprotection in tauopathies.
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