Molecular Nutrition Research, Interdisciplinary Research Center, Justus-Liebig-University of Giessen, Heinrich-Buff-Ring 26-32, D-35392, Giessen, Germany.
Molecular Nutrition Research, Interdisciplinary Research Center, Justus-Liebig-University of Giessen, Heinrich-Buff-Ring 26-32, D-35392, Giessen, Germany.
Biochem Biophys Res Commun. 2023 Sep 17;673:16-22. doi: 10.1016/j.bbrc.2023.06.064. Epub 2023 Jun 19.
Alzheimer's disease (AD) is a neurodegenerative disorder and the most common form of dementia. The pathogenesis is a complex process, in which the proteotoxicity of amyloid-β (Aβ) was identified as a major factor. 4-Phenylbutyric acid (4-PBA) is an aromatic short-chain fatty acid that may attenuate Aβ proteotoxicity through its already shown properties as a chemical chaperone or by inhibition of histone deacetylases (HDACs). In the present study, we investigated the molecular effects of 4-PBA on Aβ proteotoxicity using the nematode Caenorhabditis elegans as a model. Computer-based analysis of motility was used as a measure of Aβ proteotoxicity in the transgenic strain GMC101, expressing human Aβ in body wall muscle cells. Aβ aggregation was quantified using the fluorescent probe NIAD-4 to correlate the effects of 4-PBA on motility with the amount of the proteotoxic protein. Furthermore, these approaches were supplemented by gene regulation via RNA interference (RNAi) to identify molecular targets of 4-PBA. 4-PBA improved the motility of GMC101 nematodes and reduced Aβ aggregation significantly. Knockdown of hsf-1, encoding an ortholog essential for the cytosolic heat shock response, prevented the increase in motility and decrease in Aβ aggregation by 4-PBA incubation. RNAi for hda-1, encoding an ortholog of histone deacetylase 2, also increased motility. Double RNAi for hsf-1 and hda-1 revealed a dominant effect of hsf-1 RNAi. Moreover, 4-PBA failed to further increase motility under hda-1 RNAi. Accordingly, the results suggest that 4-PBA attenuates Aβ proteotoxicity in an AD-model of C. elegans through activation of HSF-1 via inhibition of HDA-1.
阿尔茨海默病（AD）是一种神经退行性疾病，也是最常见的痴呆症形式。其发病机制是一个复杂的过程，其中淀粉样蛋白-β（Aβ）的蛋白毒性被确定为主要因素。4-苯丁酸（4-PBA）是一种芳香族短链脂肪酸，通过其作为化学伴侣的已有特性或通过抑制组蛋白去乙酰化酶（HDACs），可能减轻 Aβ 的蛋白毒性。在本研究中，我们使用秀丽隐杆线虫作为模型，研究了 4-PBA 对 Aβ 蛋白毒性的分子影响。基于计算机的运动分析被用作表达人 Aβ 在体壁肌肉细胞中的转基因株系 GMC101 的 Aβ 蛋白毒性的测量。使用荧光探针 NIAD-4 定量 Aβ 聚集，以将 4-PBA 对运动的影响与蛋白毒性蛋白的量相关联。此外，还通过 RNA 干扰（RNAi）进行基因调控来补充这些方法，以确定 4-PBA 的分子靶标。4-PBA 改善了 GMC101 线虫的运动能力，并显著减少了 Aβ 聚集。hsf-1 的 RNAi 阻断了 4-PBA 孵育时运动能力的增加和 Aβ 聚集的减少，hsf-1 编码细胞溶质热休克反应所必需的同源物。编码组蛋白去乙酰化酶 2 的同源物 hda-1 的 RNAi 也增加了运动能力。hsf-1 和 hda-1 的双重 RNAi 显示出 hsf-1 RNAi 的优势效应。此外，在 hda-1 RNAi 下，4-PBA 未能进一步增加运动能力。因此，结果表明，4-PBA 通过抑制 HDA-1 激活 HSF-1 来减轻 AD 模型秀丽隐杆线虫中的 Aβ 蛋白毒性。
