Aging-associated REG proteasome decline predisposes to tauopathy

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