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

TitleX-linked ubiquitin-specific peptidase 11 increases tauopathy vulnerability in women.
Publication TypeJournal Article
Year of Publication2022
AuthorsYan Y, Wang X, Chaput D, Shin M-K, Koh Y, Gan L, Pieper AA, Woo J-AA, Kang DE
JournalCell
Volume185
Issue21
Pagination3913-3930.e19
Date Published2022 Oct 13
ISSN1097-4172
KeywordsAlzheimer Disease, Animals, Brain, Disease Models, Animal, Female, Humans, Male, Mice, Mice, Transgenic, Sex Characteristics, tau Proteins, Tauopathies, Thiolester Hydrolases, Ubiquitin-Specific Proteases
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.

DOI10.1016/j.cell.2022.09.002
Alternate JournalCell
PubMed ID36198316
PubMed Central IDPMC9588697
Grant ListI01 BX004680 / BX / BLRD VA / United States
R01 AG059721 / AG / NIA NIH HHS / United States
R01 AG067741 / AG / NIA NIH HHS / United States
R01 NS122350 / NS / NINDS NIH HHS / United States
P30 AG072959 / AG / NIA NIH HHS / United States
RF1 AG053060 / AG / NIA NIH HHS / United States
P50 AG025688 / AG / NIA NIH HHS / United States