X-linked ubiquitin-specific peptidase 11 increases tauopathy vulnerability in women
Open accessAbstract
Although women experience significantly higher tau burden and increased risk for Alzheimer's disease (AD) than men, the underlying mechanism for this vulnerability has not been explained. Here, we demonstrate through in vitro and in vivo models, as well as human AD brain tissue, that X-linked ubiquitin specific peptidase 11 (USP11) augments pathological tau aggregation via tau deubiquitination initiated at lysine-281. Removal of ubiquitin provides access for enzymatic tau acetylation at lysines 281 and 274. USP11 escapes complete X-inactivation, and female mice and people both exhibit higher USP11 levels than males. Genetic elimination of usp11 in a tauopathy mouse model preferentially protects females from acetylated tau accumulation, tau pathology, and cognitive impairment. USP11 levels also strongly associate positively with tau pathology in females but not males. Thus, inhibiting USP11-mediated tau deubiquitination may provide an effective therapeutic opportunity to protect women from increased vulnerability to AD and other tauopathies.
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USP11 increases susceptibility to tauopathy in women.
“peptidase 11 (USP11) has been shown to increase susceptibility to tauopathy in women.”
From Role of Tau Protein in Neurodegenerative Diseases and Development of Its Targeted Drugs: A Literature Review (2024) · cites this paper as [136]
USP11 initiates tau protein deubiquitination via lysine-281.
“Yan Y et al. demonstrated that USP11 initiates tau protein deubiquitination via lysine-281.”
From Role of Tau Protein in Neurodegenerative Diseases and Development of Its Targeted Drugs: A Literature Review (2024) · cites this paper as [136]
USP11 levels in females are strongly associated with tau pathology.
“USP11 levels in females are also strongly associated with tau pathology”
From Role of Tau Protein in Neurodegenerative Diseases and Development of Its Targeted Drugs: A Literature Review (2024) · cites this paper as [136]
Enhanced pathological tau protein aggregation and deubiquitination activate a pathway for tau protein acetylation on lysines 281 and 274.
“Enhanced pathological tau protein aggregation and deubiquitination activate a pathway for tau protein acetylation on lysines 281 and 274.”
From Role of Tau Protein in Neurodegenerative Diseases and Development of Its Targeted Drugs: A Literature Review (2024) · cites this paper as [136]
In a mouse model of tauopathy, elimination of the USP11 gene preferentially protects females against acetylated tau accumulation, tau pathology, and cognitive impairment.
“In a mouse model of tauopathy, elimination of the USP11 gene preferentially protects females against acetylated tau accumulation, tau pathology, and cognitive impairment.”
From Role of Tau Protein in Neurodegenerative Diseases and Development of Its Targeted Drugs: A Literature Review (2024) · cites this paper as [136]
Inhibition of USP11-mediated deubiquitination of tau protein may provide an effective therapeutic approach to protect females from increased susceptibility to AD and other tauopathies.
“the inhibition of USP11-mediated deubiquitination of tau protein may provide an effective therapeutic approach to protect females from increased susceptibility to AD and other tauopathies [136].”
From Role of Tau Protein in Neurodegenerative Diseases and Development of Its Targeted Drugs: A Literature Review (2024) · cites this paper as [136]
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- Authors
- Yan, Y., Wang, X., Chaput, D., Shin, M.-K., Koh, Y., Gan, L., Pieper, A. A., Woo, J.-A. A., & Kang, D. E.
- Affiliations
- University of South Florida (US)
- Case Western Reserve University (US)
- University Hospitals of Cleveland (US)
- Weill Cornell Medicine (US)
- Corresponding author
- Woo, Jung-A.A.
- Kang, David E.
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2022-10
- Volume
- 185
- Issue
- 21
- Pages
- 3913-3930.e19
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC9588697
- OpenAlex
- W4300979984
- Cited by
- 144
- References
- 116
- Citations by year
- 2026: 32 · 2025: 44 · 2024: 27 · 2023: 34 · 2022: 7
- FWCI
- 17.78
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Digital Commons - University of South Florida (University of South Florida) (submittedVersion, cc-by)
- Seoul National University Open Repository (Seoul National University) (submittedVersion)
- Funders
- Case Western Reserve University (19PABH134580006)
- National Institutes of Health (1P30AG072959, R01AG059721, R01AG067741, R01NS122350, RF1AG053060)
- U.S. Department of Veterans Affairs (BX004680)
- American Heart Association
- Alzheimer's Disease Research Center, Emory University (P50 AG025688)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- USP11, tau acetylation, tauopathy, Alzheimer's disease, sex differences, X-inactivation escape, cognitive impairment, therapeutic target
- MeSH terms
- Alzheimer Disease, Animals, Brain, Disease Models, Animal, Female, Humans, Male, Mice, Transgenic, Sex Characteristics, Thiolester Hydrolases, tau Proteins, Tauopathies, Mice, Ubiquitin-Specific Proteases
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