Researchers from Texas Children’s Hospital and Baylor College of Medicine have identified new tau regulators that could be viable new therapeutic targets effective against a range of tauopathies including Alzheimer’s disease. The research, led by Huda Zoghbi, MD, a professor at Baylor and founding director of the Jan and Dan Duncan Neurological Research Institute (Duncan NRI) at Texas Children’s Hospital was published last week in Neuron, and involved multidisciplinary team that included computational modeling and the use of RNAi for downregulating genes, and CRISPR technology for a small subset of genes.
The team began their research by performing an unbiased screen employing computational modeling and prediction analysis of the more than 17,000 known human genes and winnowed that to a collection of 6,600 genes that were deemed as druggable, defined as those proteins whose functional domains can be modified by chemical compounds. The team then employed a cross-species approach using mammalian cells and fruit flies to query the 6,600 genes to find those that impact tau levels, using both RNAi and CRISPR technologies to perform to down-regulate the genes.
“Our strategy of performing parallel loss-of-function genetic screens in mammalian cells and fruit flies allowed us to select targets that showed up as top hits in both species,” said Ismael Al-Ramahi, PhD, assistant professor at Baylor and study co-author.
Of the 11 proteins newly identified as tau regulators, three of them—ubiquitin-specific protease 7 (USP 7), RING-Type E3 Ubiquitin Transferase (RNF130), and RING-Type E3 Ubiquitin Transferase (RN149)—converged on the ubiquitin protein degradation pathway. The cross-species approach “led us to reliable tau regulators whose functions are critical enough to be evolutionarily conserved from fruit flies to humans,” noted Al-Ramahi.
Previous studies have investigated the role played by C-terminus of Hsc70-interacting protein (CHIP), which has been implicated as a regulator of tau turnover as well as an important protein in the selective elimination of abnormal tau species. The Duncan NRI team, delving into the activity of the three newly found proteins have begun to unravel how they help regulate the ubiquitin pathway.
First, the team noted that USP7 stabilizes tau by protecting it from the CHIP-mediated degradation. In addition, RNF130 and RNF149 decrease the levels of the tau degrader (CHIP) and that their inhibition increases CHIP which in turn decreases tau levels. The investigators then progressed to testing their target genes in mouse models that overexpress mutant tau to see if they regulate tau levels in the brain.
“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,” said Ji-Yoen Kim, assistant professor in the Zoghbi lab and lead author of the study. “We also saw a decrease in other tell-tale signs of tau pathology and neuro-inflammation. 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.”
The notable finding of the study, the authors noted, is despite USP7, RNF130, and RNF149 never having been linked before, the fact that their functions all converged on CHIP lends further weight to the important role CHIP plays in keeping tau levels in check.
“While previous studies have used antisense oligonucleotides to target human tau mRNA, we rationalized that identifying tau regulators that can be inhibited by small-molecule drugs will be worthwhile given the likelihood that treatments to prevent dementia are best initiated in the pre-symptomatic phase and are likely to go on for decades,” Zoghbi said. “This discovery opens the exciting possibility of leveraging small-molecule inhibitors to lower tau levels and hopefully, prevent memory deficits in those at risk for Alzheimer’s disease and other tauopathies.”