As our life expectancy continues to increase, we can expect more people to be affected by neurodegenerative diseases in the future. Tauopathies, such as Alzheimer’s Disease, are a group of neurodegenerative diseases that involve an accumulation of tau protein. This eventually results in massive brain cell loss. The underlying causes of these disorders are not well understood and there is no treatment available.
Researchers at Baylor College of Medicine, Texas Children’s Hospital and the University of Texas wanted to perform an unbiased screening to identify genes that could reduce tau levels. Researchers at Baylor College of Medicine and Texas Children’s Hospital conducted an unbiased screen to find genes whose inhibition can reduce the levels of tau protein.
The study was directed by Dr. Huda Zhghbi. She is a professor of molecular, human genetics, and neurosciences at Baylor University and the founding director of Texas Children’s Jan and Dan Duncan Neurological Research Institute. This study involved collaborations between other Duncan NRI Faculty, Dr. Juan Botas, and Dr. Zhandong Liu.
Three new tau regulators are revealed by a cross-species screen
The Liu lab first performed computational modeling and predicted analysis of 17,000 known human genes. It then generated a compendium containing 6,600 genes that could be manipulated by chemical compounds.
The study was led by Dr. Jiyoen Kim. She is an assistant professor in neuroscience at the Zoghbi laboratory and the lead author.
In both screens, RNA interference was used to reduce the activity of genes, while CRISPR technology was used in the cell-based screening.
Our strategy of parallel screening in mammalian and fruit fly cells allowed us to select top targets in both species,” explained Dr. Ismael al-Ramahi. He is an assistant professor of human and molecular genetics at Baylor University and a member the Duncan NRI.
They found 11 new tau regulators using this approach. Three of these converged on ubiquitin degradation pathway – USP7, RNF130 and RN149. The team investigated these proteins to determine how they regulate the ubiquitin protein degradation pathway.
USP7, and RNF130 and RNF149 regulate the tau levels through the CHIP system
The team found that USP7 protects tau from degradation by CHIP. RNF130, RNF149 and CHIP degrader levels were also decreased by RNF130, RNF149. The team tested if these target gene can regulate CHIP levels and tau in the brain by turning off their expression in adult mouse overexpressing mutant tau.
Kim stated that “Turning down the expression of USP7 or RNF130 in adult mice with Tauopathy increased CHIP levels and reduced tau proteins.” We also noticed a reduction in the other telltale signs of neuro-inflammation and tau-mediated injury. These mice also performed at the same level as normal mice of similar age in learning and memory tasks. This is a clear indication that increasing CHIP levels, along with a reduction in tau levels, can improve neuronal function and overall brain functions in these mice.
These three proteins were never linked before but their functions are similar, which highlights CHIP’s central role in keeping tau levels under control.
Zoghbi explained, “We rationalized it would be worth while to identify tau regulators which can be inhibited with small-molecule drugs given that dementia prevention treatments are most effective when initiated during the pre-symptomatic stage and will likely continue for many decades.” We are thrilled to have identified three targets which reduce tau levels and improve disease characteristics, learning and memory. This discovery opens up the possibility of using small-molecule inhibitors that lower tau levels to prevent memory deficits and Alzheimer’s and other tauopathies.
Other participants in the study are Bakhos Tadros, Lorena Garaicoechea and Hyun-Hwan Sonn. They are associated with Baylor College of Medicine and Texas Children’s Hospital.
The JPB Foundation and the Robert A. and Renee E. Belfer Family Foundation supported this research, as did the Ting Tsung and Wei Fong Chao Foundation and the Howard Hughes Medical Institute.
