Researchers here report on an investigation of mechanisms regulating the turnover of tau protein in brain cells. The hope is to find approaches that will more aggressively clear the tau aggregates found in neurodegenerative conditions via the usual cell maintenance processes responsible for breaking down excess proteins, such as autophagy and proteasomal degradation. It is far too early to say how promising this approach might turn out to be at the end of the day, but the initial exploration is interesting.
A novel screening approach led researchers to 11 new in vivo validated tau regulators. Of these, three targets - ubiquitin-specific protease 7 (USP 7), RING-Type E3 Ubiquitin Transferase (RNF130), and RING-Type E3 Ubiquitin Transferase (RNF149) - converged on the ubiquitin protein degradation pathway. The majority of intracellular proteins within all tissues are degraded by the ubiquitin-proteasomal pathway. This is a complex, tightly regulated process involving several discrete and successive steps. Ubiquitin molecules are first activated and transferred to carrier proteins. Multiple ubiquitin molecules are attached to the protein substrate via a group of enzymes called the E3 ubiquitin ligases. Finally, the ubiquitinated substrate is degraded.
Previous studies have implicated the ubiquitin ligase, CHIP (C-terminus of Hsc70-interacting protein), as an important regulator of tau turnover and a critical player in the selective elimination of abnormal tau species. Interestingly, in this study, the researchers discovered that USP7 stabilizes tau by protecting it from CHIP-mediated degradation. They also found that RNF130 and RNF149 decrease the levels of the tau degrader (CHIP) and that their inhibition increases CHIP which in turn decreases tau levels. To test if these target genes can regulate CHIP and tau levels in the brain, the team turned off their expression in adult mice that overexpress mutant tau.
"Turning off the expression of USP7, RNF130, or RNF149 in adult mice with tauopathy using a doxycycline-inducible system increased CHIP level, and reduced total and phosphorylated-tau proteins. We also saw a decrease in other tell-tale signs of tau pathology and neuroinflammation. Most excitingly, these mice performed as well as age-matched normal mice in tasks that require learning and memory - a strong indicator that increasing CHIP levels in addition to a concomitant reduction in tau levels can improve neuronal and overall brain function in these mice."