Evolutionarily Conserved Regulators of Tau Identify Targets for New Therapies

Authors

Jiyoen Kim
Maria de Haro
Ismael Al-Ramahi
Lorena Laura Garaicoechea
Hyun-Hwan Jeong
Jun Young Sonn
Bakhos Tadros
Zhandong Liu
Juan Botas
Huda Yahya Zoghbi

Language

English

Publication Date

3-15-2023

Journal

Neuron

DOI

10.1016/j.neuron.2022.12.012

PMID

36610398

Abstract

Tauopathies are neurodegenerative diseases that involve the pathological accumulation of tau proteins; in this family are Alzheimer disease, corticobasal degeneration, and chronic traumatic encephalopathy, among others. Hypothesizing that reducing this accumulation could mitigate pathogenesis, we performed a cross-species genetic screen targeting 6,600 potentially druggable genes in human cells and Drosophila. We found and validated 83 hits in cells and further validated 11 hits in the mouse brain. Three of these hits (USP7, RNF130, and RNF149) converge on the C terminus of Hsc70-interacting protein (CHIP) to regulate tau levels, highlighting the role of CHIP in maintaining tau proteostasis in the brain. Knockdown of each of these three genes in adult tauopathy mice reduced tau levels and rescued the disease phenotypes. This study thus identifies several points of intervention to reduce tau levels and demonstrates that reduction of tau levels via regulation of this pathway is a viable therapeutic strategy for Alzheimer disease and other tauopathies.

Keywords

Adult, Animals, Humans, Mice, Alzheimer Disease, Brain, Drosophila, tau Proteins, Tauopathies, Ubiquitin-Specific Peptidase 7, RNF130, RNF149, USP7, genetic screens, modifier, neurodegeneration, tau levels, ubiquitination

Published Open-Access

yes

Recommended Citation

Kim, Jiyoen; de Haro, Maria; Al-Ramahi, Ismael; et al., "Evolutionarily Conserved Regulators of Tau Identify Targets for New Therapies" (2023). Duncan NRI Faculty and Staff Publications. 124.
https://digitalcommons.library.tmc.edu/duncar_nri_pub/124