2019 — 2021 |
Woo, Jung A |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Novel Role of ?-Arrestins in Tauopathy @ University of South Florida
The major defining pathological hallmarks of Alzheimer?s disease (AD) are the accumulation of amyloid ? (A?) and hyperphosphorylated tau. Multiple GPCRs (i.e, ?2AR, GPR3, AT2R, CXCR2, & NMDARs) have been shown to play integral roles in AD pathogenesis. However, it is unclear as to how a diverse array of GPCRs all positively impinge on A? and tau pathogenesis as well as neurodegeneration in AD. Given that GPCRs share a common mechanism of action via ?-arrestin scaffolding signaling complexes, the central hypothesis is that the actions of ?-arrestins downstream of GPCRs directly impact AD pathogenesis. ?-arrestins exist in three distinct states in cells; 1) free unbound, 2) GPCR-bound, and 3) microtubule-bound, each with different signaling capability. Previous studies have shown that ?-arrestins are upregulated in AD brains and that ?- arrestins promote A? pathogenesis. However, it is unknown whether and how ?-arrestins pathogenically impinge on tauopathy and neurodegeneration in AD. Preliminary data indicate that ?-arrestin oligomers promote tauopathy via 2 distinct mechanisms: 1) directly competing with tau for binding to microtubules (MT), thereby deregulating MT dynamics; 2) inhibiting tau clearance by deregulating the autophagy machinery. By utilizing molecular, cell biological, biochemical, electrophysiological, behavioral, viral, and histochemical tools, this proposal will 1) validate the role of ?-arrestins in tauopathy in vivo, 2) validate the role of ?-arrestins in tau/microtubule dynamics, and 3) investigate the role of ?- arrestins in p62-mediated autophagy and tau turnover. This proposal will validate whether ?- arrestins and their oligomeric status serve as promising therapeutic targets to mitigate tau pathogenesis.
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0.901 |
2020 — 2021 |
Kang, David E [⬀] Woo, Jung A |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Deubiquitinase Usp11 in Tau Regulation and Age-Related Tauopathy @ University of South Florida
The microtubule-associated protein tau (MAPT) aggregates and accumulates in multiple neurodegenerative diseases, including Alzheimer?s disease (AD). Abnormal tau accumulation leads to oligomerization and formation of neurofibrillary tangles associated with neuronal loss, synaptic dysfunction, and cognitive impairments. While tau undergoes different post-translational modifications including phosphorylation, acetylation, and ubiquitination, ubiquitination is critical for tau turnover via the ubiquitin-proteasome system and autophagy-lysosome pathways. Tau is known to be ubiquitinated by various E3 ligases, including CHIP, TRAF6, and MARCH7. However, very little is known about the role of deubiquitinases (DUBs) in the regulation of tau function, turnover, or tauopathy. The human genome encodes >90 DUBs. Ubiquitin specific peptidases (USPs) are the largest family of DUBs comprising ~50 members in humans. Of these, 27 are expressed in the CNS. Our results from an unbiased screen of CNS-expressed DUBs identified USP11 and USP13 as positive regulators of tau. By taking advantage of mouse models and human postmortem tissues together with molecular, cell biological, imaging, biochemical, electrophysiological, behavioral, viral, histochemical, and recombinant protein toolsets, this proposal will 1. validate the role of USP11 in tau pathogenesis as a function of age and sex in vivo, and 2. determine the mechanistic basis of USP11 in tau stability, aggregation, and toxicity in genetically modified neurons and in vitro systems. Successful conclusion of these studies will determine the significant contribution of USP11, and its DUB activity, to tauopathy in humans and mice as a function of aging and sex. USP11 levels could in part account for potential sex differences in severity of tauopathy in humans and mice. Moreover, these results will provide novel mechanistic insights to USP11 DUB activity, in concert with RanBP9, in tau modification and toxicity.
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0.901 |