Results of a cross-species genetic screen published in Neuron “Evolutionarily conserved regulators of tau identify targets for new therapies” have identified 11 genes that regulate levels of tau protein. Abnormal accumulation of misfolded tau tangles in the brain is a common manifestation among diverse neurodegenerative diseases that are categorized under the umbrella of “tauopathies.” Currently, there are no treatments available for tauopathies, which include Alzheimer’s disease, corticobasal degeneration, chronic traumatic encephalopathy, along with other forms of dementia.
“This study identifies several points of intervention to reduce tau levels and demonstrates that reduction of tau levels via regulation of the pathway is a viable therapeutic technique for Alzheimer’s and other tauopathies,” the authors noted.
Huda Zoghbi, PhD, professor of human and molecular genetics, neuroscience, and neurology at the Baylor College of Medicine, computational biologist Hyun-Hwan Jeong, PhD, and research associate Lorena Garaicoechea, PhD, are the other authors of the study.
Tau proteins include six isoforms that are all generated through alternative splicing of a gene called microtubule-associated protein tau. All 6 tau proteins stabilize microtubules and are crucial in cellular transport within neurons. Excessive phosphorylation of tau results in its accumulation in Alzheimer’s disease where it forms neurofibrillary tangles.
Based on the hypothesis that decreasing the accumulation of tau could mitigate tauopathies, the investigators screened 6,600 potential drug targets in human cells and in fruit flies and validated 83 hits in cells as well as further validation of 11 hits in vivo in the mouse brain. Knocking down the expression of these 11 regulators successfully reduced the degrees of tau in the mice.
To decrease disease phenotypes, the researchers knocked down three tau regulators (USP7, RNF130, and RNF149) in an adult mouse model of tauopathy. In addition to reducing pathological tau species (phosphorylated tau and tau oligomers) this reduced the hallmarks of tauopathies including memory deficit, tau seeding activity, and abnormal activation of microglia and astrocytes.
The researchers found USP7, RNF130, and RNF149 converge on a known regulator of tau, an E3 ubiquitin ligase called CHIP. The authors showed that while USP7 stabilizes tau by suppressing CHIP-mediated ubiquitination of tau that marks the protein for degradation, RNF130 and RNF149 accomplish tau stabilization by degrading CHIP itself. These findings indicate CHIP plays a pivotal role in regulating tau levels.
“Even the modest suppression of these genes in adult tauopathy mice benefited the learning and memory deficits, proving that reducing tau levels could possibly be an attractive therapeutic strategy for tauopathies to delay or prevent disease progression,” the authors concluded. The team is positive that future studies that clarify the regulation of tau levels will help discover novel drug targets for Alzheimer’s disease.