Aging-associated REGγ proteasome decline predisposes to tauopathy.

The REGγ-20S proteasome is an ubiquitin- and ATP-independent degradation system, targeting selective substrates, possibly helping to regulate aging. The studies we report here demonstrate that aging-associated REGγ decline predisposes to decreasing tau turnover, as in a tauopathy. The REGγ proteasome promotes degradation of human and mouse tau, notably phosphorylated tau and toxic tau oligomers that shuttle between the cytoplasm and nuclei. REGγ-mediated proteasomal degradation of tau was validated in 3- to 12-month-old REGγ KO mice, REGγ KO;PS19 mice, and PS19 mice with forebrain conditional neuron-specific overexpression of REGγ (REGγ OE) and behavioral abnormalities. Coupled with tau accumulation, we found with REGγ-deficiency, neuron loss, dendrite reduction, tau filament accumulation, and microglial activation are much more prominent in the REGγ KO;PS19 than the PS19 model. Moreover, we observed that the degenerative neuronal lesions and aberrant behaviors were alleviated in REGγ OE;PS19 mice. Memory and other behavior analysis substantiate the role of REGγ in prevention of tauopathy-like symptoms. In addition, we investigated the potential mechanism underlying aging-related REGγ decline. This study provides valuable insights into the novel regulatory mechanisms and potential therapeutic targets for tau-related neurodegenerative diseases.

Intranasal administration of white tea alleviates the olfactory function deficit induced by chronic unpredictable mild stress.

CONTEXT: White tea [Camellia sinensis (L) O.Ktze. (Theaceae)] is popular in Asia, but its benefits on olfactory injury are unknown. OBJECTIVE: The present study explores the effects of white tea on the olfactory injury caused by chronic unpredictable mild stress (CUMS). MATERIALS AND METHODS: C57BL/6J mice (WT) were exposed to CUMS. CUMS mice (CU) were intranasally treated with white tea extract [low tea (LT), 20 mg/kg; high tea (HT), 40 mg/kg] and fluoxetine (CF, 20 mg/kg) for 7 days. Several behavioural tests were conducted to assess depression and olfactory function. The transmission electron microscope (TEM) and semi-quantitative reverse transcription PCR were performed separately to observe the changes of related structures and genes transcription level. RESULTS: The depressive behaviours of the LT and HT mice were reversed. The latency time of the buried food pellet test decreased from 280 s (CU) to 130 s (HT), while the olfactory sensitivity and olfactory avoidance test showed that the olfactory behaviours disorder of LT and HT mice were alleviated. The white tea increased the A490 nm values of the cortisol treated cells from 0.15 to 1.4. Reduced mitochondrial and synaptic damage in the olfactory bulb (OB), enhanced expression of the brain-derived neurotrophic factor (BDNF) and olfactory marker protein (OMP) were observed in the LT and HT mice. CONCLUSIONS AND DISCUSSION: White tea has the potential in curing the olfactory deficiency related to chronic stress. It lays the foundation for the development of new and reliable drug to improve olfactory.

Proteasome activator PA28γ-dependent degradation of coronavirus disease (COVID-19) nucleocapsid protein.

The nucleocapsid protein is significant in the formation of viral RNA of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), accounting for the largest proportion of viral structural proteins. Here, we report for the first time that the 11S proteasomal activator PA28γ regulates the intracellular abundance of the SARS-CoV-2 N protein (nCoV N). Furthermore, we have identified proteasome activator PA28γ as a nCoV N binding protein by co-immunoprecipitation assay. As a result of their interaction, nCoV N could be degraded by PA28γ-20S in vitro degradation assay. This was also demonstrated by blocking de novo protein synthesis with cycloheximide. The stability of nCoV N in PA28γ-knockout cells was greater than in PA28γ-wildtype cells. Notably, immunofluorescence staining revealed that knockout of the PA28γ gene in cells led to the transport of nCoV N from the nucleus to the cytoplasm. Overexpression of PA28γ enhanced proteolysis of nCoV N compared to that in PA28γ-N151Y cells containing a dominant-negative PA28γ mutation, which reduced this process. These results suggest that PA28γ binding is important in regulating 20S proteasome activity, which in turn regulates levels of the critical nCoV N nucleocapsid protein of SARS-CoV-2, furthering our understanding of the pathogenesis of COVID-19.