Department of Cell Biology, Emory University School of Medicine, Atlanta, GA 30322.
Department of Genetics, Cell Biology, and Anatomy, University of Nebraska Medical Center, Omaha, NE 68198.
Proc Natl Acad Sci U S A. 2020 Nov 17;117(46):29133-29143. doi: 10.1073/pnas.2013552117. Epub 2020 Nov 2.
Tauopathies are a class of neurodegenerative diseases associated with pathological tau. Despite many advances in our understanding of these diseases, the direct mechanism through which tau contributes to neurodegeneration remains poorly understood. Previously, our laboratory implicated the histone demethylase LSD1 in tau-induced neurodegeneration by showing that LSD1 localizes to pathological tau aggregates in Alzheimer's disease cases, and that it is continuously required for the survival of hippocampal and cortical neurons in mice. Here, we utilize the P301S tauopathy mouse model to demonstrate that pathological tau can exclude LSD1 from the nucleus in neurons. In addition, we show that reducing LSD1 in these mice is sufficient to highly exacerbate tau-mediated neurodegeneration and tau-induced gene expression changes. Finally, we find that overexpressing LSD1 in the hippocampus of tauopathy mice, even after pathology has formed, is sufficient to significantly delay neurodegeneration and counteract tau-induced expression changes. These results suggest that inhibiting LSD1 via sequestration contributes to tau-mediated neurodegeneration. Thus, LSD1 is a promising therapeutic target for tauopathies such as Alzheimer's disease.
tau 病是一类与病理性 tau 相关的神经退行性疾病。尽管我们对这些疾病的认识有了很多进展，但 tau 导致神经退行性变的确切机制仍知之甚少。以前，我们实验室通过显示 LSD1 定位于阿尔茨海默病病例中的病理性 tau 聚集体，以及 LSD1 连续需要存活于海马体和皮质神经元，表明 LSD1 参与 tau 诱导的神经退行性变，从而暗示 LSD1 在 tau 诱导的神经退行性变中起作用。在这里，我们利用 P301S tau 病模型证明病理性 tau 可以将 LSD1 从神经元的核内排斥出去。此外，我们还表明，在这些小鼠中降低 LSD1 的表达足以高度加剧 tau 介导的神经退行性变和 tau 诱导的基因表达变化。最后，我们发现即使在病理形成后，在 tau 病小鼠的海马体中过表达 LSD1 也足以显著延迟神经退行性变并对抗 tau 诱导的表达变化。这些结果表明，通过隔离抑制 LSD1 有助于 tau 介导的神经退行性变。因此，LSD1 是阿尔茨海默病等 tau 病的一个有前途的治疗靶点。
