Early whole-body mutant huntingtin lowering averts changes in proteins and lipids important for synapse function and white matter maintenance in the LacQ140 mouse model.
Early whole-body mutant huntingtin lowering averts changes in proteins and lipids important for synapse function and white matter maintenance in the LacQ140 mouse model.
复制标题
早期全身突变亨廷顿蛋白降低可避免蛋白质和脂质的变化，这对 LacQ140 小鼠模型中的突触功能和白质维持很重要。
DOI：
10.1101/2023.01.26.525697
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Kegel-Gleason,KimberlyB
中科院分区：
文献类型：
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作者：
Shing,Kai;Sapp,Ellen;Boudi,Adel;Liu,Sophia;Seeley,Connor;Marchionini,Deanna;DiFiglia,Marian;Kegel-Gleason,KimberlyB
HTT 基因外显子 1 中三联体重复序列的扩展会导致亨廷顿病 (HD)。突变 HTT 蛋白 (mHTT) 具有多种异常相互作用，具有多种多形性效应。降低 mHTT 是治疗 HD 的一种有前途的方法，但尚不清楚何时应开始降低、需要降低多少以及应持续多长时间才能获得益处。此外，尚未评估 mHTT 降低对脑脂质的影响。使用 mHtt 诱导小鼠模型，我们分析了在不同年龄开始并持续不同时间段的 mHtt 降低。纹状体细胞质和突触区室中的 mHTT 蛋白减少 38-52%；然而，在 12 月龄时形成聚集体的核和核周区域，mHTT 略有降低。 9 个月大的 LacQ140 小鼠的总纹状体脂质减少，并通过 mHttlowering 得到保留。对白质结构和功能很重要的亚类包括神经酰胺 (Cer)、鞘磷脂 (SM) 和单半乳糖二酰基甘油 (MGDG)，有助于降低总脂质。 LacQ140 小鼠中的磷脂酰肌醇 (PI)、磷脂酰丝氨酸 (PS) 和双甲基磷脂酸 (BisMePA) 也发生了变化。除神经酰胺外的所有亚类的水平均通过 mHttlowering 得以保留。 mRNA 表达谱表明转录机制导致髓磷脂脂质的变化，并且一些但不是全部的变化可以通过 mHttlowering 来预防。我们的研究结果表明，早期持续减少 mHtt 可以防止特定纹状体蛋白和大多数脂质水平的变化，但错误折叠的、抗降解形式的 mHTT 会阻碍长期的一些益处。
Expansion of a triplet repeat tract in exon 1 of theHTTgene causes Huntington’s disease (HD). The mutant HTT protein (mHTT) has numerous aberrant interactions with diverse, pleiomorphic effects. Lowering mHTT is a promising approach to treat HD, but it is unclear when lowering should be initiated, how much is necessary, and what duration should occur to achieve benefits. Furthermore, the effects of mHTT lowering on brain lipids have not been assessed. Using a mHtt-inducible mouse model, we analyzed mHttlowering initiated at different ages and sustained for different time-periods. mHTT protein in cytoplasmic and synaptic compartments of the striatum was reduced 38-52%; however, there was minimal lowering of mHTT in nuclear and perinuclear regions where aggregates formed at 12 months of age. Total striatal lipids were reduced in 9-month-old LacQ140 mice and preserved by mHttlowering. Subclasses important for white matter structure and function including ceramide (Cer), sphingomyelin (SM), and monogalactosyldiacylglycerol (MGDG), contributed to the reduction in total lipids. Phosphatidylinositol (PI), phosphatidylserine (PS), and bismethyl phosphatidic acid (BisMePA) were also changed in LacQ140 mice. Levels of all subclasses except ceramide were preserved by mHttlowering. mRNA expression profiling indicated that a transcriptional mechanism contributes to changes in myelin lipids, and some but not all changes can be prevented by mHttlowering. Our findings suggest that early and sustained reduction in mHttcan prevent changes in levels of select striatal proteins and most lipids, but a misfolded, degradation-resistant form of mHTT hampers some benefits in the long term.