Prion protein (PrP) can cause dementia and death when abnormally folded into self-propagating conformations. Previous studies have shown that depletion of PrP in the brain can block disease development. Based on this antecedent, Neumann et al. conceived a strategy to epigenetically silence PrP expression in the mouse brain via DNA methylation. They generated a small non-enzymatic editor called coupled histone tail for autoinhibition release of methyltransferase (CHARM). CHARM, which comprises a fusion between a histone H3 tail and a DNMT3L noncatalytic domain, can recruit endogenous DNA methyltransferases and epigenetically silence specific targets when coupled with a DNA-binding domain. The advantages of CHARM include a small transgene size and low cytotoxicity. Using systemic injection of adeno-associated virus to deliver CHARM into the brain, the authors were able to broadly repress PrP expression. Interestingly, they also devised a way to achieve transient activity of CHARM via a kinetically tuned self-silencing approach. It will be interesting to try to use CHARM in other pathogenic contexts to target disease-causing proteins, not only in the brain (for example, other neurodegenerative disorders caused by toxic protein aggregates) but also in other organs. Hopefully, these studies will pave the way for new therapeutic avenues.

Original reference: Science https://doi.org/10.1126/science.ado7082 (2024)

朊病毒蛋白（PrP）异常折叠成自我繁殖构象时可导致痴呆和死亡。先前的研究表明，大脑中 PrP 的消耗可以阻止疾病的发展。基于这个先例，Neumann 等人。设想了一种通过 DNA 甲基化在表观遗传上沉默小鼠大脑中 PrP 表达的策略。他们生成了一种小型非酶编辑器，称为耦合组蛋白尾，用于甲基转移酶的自动抑制释放（CHARM）。 CHARM 由组蛋白 H3 尾部和 DNMT3L 非催化结构域之间的融合体组成，当与 DNA 结合结构域偶联时，可以招募内源性 DNA 甲基转移酶并在表观遗传上沉默特定靶标。 CHARM 的优点包括转基因尺寸小和细胞毒性低。通过全身注射腺相关病毒将 CHARM 传递到大脑中，作者能够广泛抑制 PrP 表达。有趣的是，他们还设计了一种通过动力学调整的自沉默方法来实现 CHARM 瞬时活性的方法。尝试在其他致病环境中使用 CHARM 来靶向致病蛋白质将会很有趣，不仅在大脑中（例如，由有毒蛋白质聚集体引起的其他神经退行性疾病），而且在其他器官中。希望这些研究将为新的治疗途径铺平道路。

Original reference: Science https://doi.org/10.1126/science.ado7082 (2024)