Department of Pathology, Case Western Reserve University, School of Medicine, Cleveland, OH, USA; Department of Molecular Medicine, USF Health College of Medicine, Tampa, FL, USA.
Department of Pathology, Case Western Reserve University, School of Medicine, Cleveland, OH, USA.
Cell. 2022 Oct 13;185(21):3913-3930.e19. doi: 10.1016/j.cell.2022.09.002. Epub 2022 Oct 4.
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.
尽管女性经历的 tau 负担明显高于男性，并且患阿尔茨海默病（AD）的风险也增加，但这种脆弱性的潜在机制尚未得到解释。在这里，我们通过体外和体内模型以及人类 AD 脑组织证明，X 连锁泛素特异性肽酶 11（USP11）通过赖氨酸-281 起始的 tau 去泛素化增强病理性 tau 聚集。去除泛素为赖氨酸 281 和 274 处的酶促 tau 乙酰化提供了途径。USP11 逃避完全的 X 失活，雌性小鼠和人都比男性表现出更高的 USP11 水平。在 tau 病模型中敲除 USP11，可优先保护雌性免受乙酰化 tau 积累、tau 病理学和认知障碍的影响。USP11 水平也与女性而非男性的 tau 病理学呈正相关。因此，抑制 USP11 介导的 tau 去泛素化可能为保护女性免受 AD 和其他 tau 病增加的易感性提供有效的治疗机会。
