Evolutionarily conserved regulators of tau identify targets for new therapies

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

doi:10.1016/j.neuron.2022.12.012

Evolutionarily conserved regulators of tau identify targets for new therapies

Neuron. 2023 Mar 15;111(6):824-838.e7. doi: 10.1016/j.neuron.2022.12.012. Epub 2023 Jan 6.

Authors

Affiliations

¹ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX 77030, USA.
² Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX 77030, USA; Center for Alzheimer's and Neurodegenerative Diseases, Baylor College of Medicine, Houston, TX 77030, USA.
³ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
⁴ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX 77030, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.
⁵ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX 77030, USA; Department of Molecular & Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA; Center for Alzheimer's and Neurodegenerative Diseases, Baylor College of Medicine, Houston, TX 77030, USA.
⁶ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX 77030, USA; Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA; Department of Neurology, Baylor College of Medicine, Houston, TX 77030, USA; Howard Hughes Medical Institute, Baylor College of Medicine, Houston, TX, USA. Electronic address: hzoghbi@bcm.edu.

PMID: 36610398
DOI: 10.1016/j.neuron.2022.12.012

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: RNF130; RNF149; USP7; genetic screens; modifier; neurodegeneration; tau levels; ubiquitination.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adult
Alzheimer Disease / metabolism
Animals
Brain / metabolism
Drosophila / metabolism
Humans
Mice
Tauopathies* / drug therapy
Tauopathies* / genetics
Tauopathies* / metabolism
Ubiquitin-Specific Peptidase 7 / metabolism
tau Proteins* / genetics
tau Proteins* / metabolism

Substances

tau Proteins
Ubiquitin-Specific Peptidase 7
USP7 protein, human