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LSD1防止海马体和皮层神经退行性变

作者:Porter-Stransky, Jeremy M. Boss, David Weinshenker

为了探究维持细胞分化的机制,我们有意删除成年小鼠的组蛋白去甲基化酶 LSD1/KDM1A。损失LSD1导致瘫痪,并伴随着广泛的海马体和皮质神经退行性变,以及学习和记忆缺陷。我们着重于海马体神经细胞死亡,以及LSD1和人类神经退行性疾病的潜在的联系,发现在退化的海马体中,损失LSD1引起常见的神经退行性通路转录变化,伴随着干细胞基因重新激活。

这些数据表明LSD1通过不恰当的转录抑制,防止神经退行性变。

令人惊讶的是,我们还发现,在海马体中的转录变化是类似于阿尔茨海默病(AD)和额颞痴呆(FTD)的情况,这些情况中,LSD1是被明确错误定位到病态的蛋白质聚集物。

这些数据增加了病态聚集物可以减弱AD和FTD中 LSD1功能的可能性。

Neurodegeneration in Lsd1 CAGG mice. ad LSD1 immunohistochemistry (IHC) of control a, c and Lsd1 CAGG b, d CA1 a, b and cortex c, d. Arrowheads highlight non-pyknotic LSD1 immunoreactive nuclei. Arrows highlight pyknotic LSD1 negative nuclei. e, f Representative images of Lsd1 CAGG mice with the terminal motor defect including hindlimb clasping e and failure to maintain posture f. g The age of each individual male (blue) or female (red) mouse at the final tamoxifen injection (start of each line) to inducibly delete Lsd1, and the number of days (length of the line) until the terminal motor defect is reached. Inset shows survival in days for each sex. Data are shown as mean survival in days ± s.e.m., n = 45 animals h, i H&E staining of tamoxifen injected Cre minus control (control) h and Lsd1 CAGG i CA1 and cortex. Insets are magnified views of non-pyknotic h and pyknotic i nuclei. CC denotes corpus callosum. jq MAP2 IHC of control j, l, n, p and Lsd1 CAGG k, m, o, q CA1 j, k, CA3 l, m, dentate gyrus n, o and cortex p, q. Brackets highlight dendrites and arrows highlight pyknotic nuclei. r, s Tau IHC of control r and Lsd1CAGG s CA1. Bracket highlights axons. tw GFAP IHC of control t, v and Lsd1 CAGG u, w hippocampus t, u and cortex v, w. Arrowheads highlight sparse astrocytes in control cortex. Insets show magnified view of representative astrocytes. xaa Merge of DAPI (red) and TUNEL (green) in control x, z and Lsd1 CAGG y, aa CA1 x, y and cortex z, aa. All IHC jw is counterstained with hematoxylin. All Lsd1 CAGG images are taken at the terminal phenotype. Scale bar = 50 µm


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原文阅读

LSD1 protects against hippocampal and cortical neurodegeneration

https://www.nature.com/articles/s41467-017-00922-9

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