| First Author | Tu J | Year | 2022 |
| Journal | J Biol Chem | Volume | 298 |
| Issue | 11 | Pages | 102571 |
| PubMed ID | 36209822 | Mgi Jnum | J:333880 |
| Mgi Id | MGI:7386142 | Doi | 10.1016/j.jbc.2022.102571 |
| Citation | Tu J, et al. (2022) Aging-associated REGgamma proteasome decline predisposes to tauopathy. J Biol Chem 298(11):102571 |
| abstractText | The REGgamma-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 REGgamma decline predisposes to decreasing tau turnover, as in a tauopathy. The REGgamma proteasome promotes degradation of human and mouse tau, notably phosphorylated tau and toxic tau oligomers that shuttle between the cytoplasm and nuclei. REGgamma-mediated proteasomal degradation of tau was validated in 3- to 12-month-old REGgamma KO mice, REGgamma KO;PS19 mice, and PS19 mice with forebrain conditional neuron-specific overexpression of REGgamma (REGgamma OE) and behavioral abnormalities. Coupled with tau accumulation, we found with REGgamma-deficiency, neuron loss, dendrite reduction, tau filament accumulation, and microglial activation are much more prominent in the REGgamma KO;PS19 than the PS19 model. Moreover, we observed that the degenerative neuronal lesions and aberrant behaviors were alleviated in REGgamma OE;PS19 mice. Memory and other behavior analysis substantiate the role of REGgamma in prevention of tauopathy-like symptoms. In addition, we investigated the potential mechanism underlying aging-related REGgamma decline. This study provides valuable insights into the novel regulatory mechanisms and potential therapeutic targets for tau-related neurodegenerative diseases. |
