Cited by 147Alzheimer's disease research and treatmentsUbiquitin and proteasome pathwaysDementia and Cognitive Impairment Research

X-linked ubiquitin-specific peptidase 11 increases tauopathy vulnerability in women

Open access
Yan, Yan, Wang, Xinming, Chaput, Dale, Shin, Min-Kyoo, Koh, Yeojung, Gan, Li, Pieper, Andrew A., Woo, Jung-A.A. +1 more·2022·Cell

Abstract

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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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.
Venue
Cell
Publisher
Elsevier BV
Published
2022-10
Volume
185
Issue
21
Pages
3913-3930.e19
ISSN
0092-8674 (ISSN-L)
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
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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