PDF(Pubmed)
Abstract：
Protein misfolding and mislocalization are common themes in neurodegenerative disorders, including motor neuron disease, and amyotrophic lateral sclerosis (ALS). Maintaining proteostasis is a crosscutting therapeutic target, including the upregulation of heat shock proteins (HSP) to increase chaperoning capacity. Motor neurons have a high threshold for upregulating stress-inducible HSPA1A, but constitutively express high levels of HSPA8. This study compared the expression of these HSPs in cultured motor neurons expressing three variants linked to familial ALS: TAR DNA binding protein 43 kDa (TDP-43)G348C, fused in sarcoma (FUS)R521G, or superoxide dismutase I (SOD1)G93A. All variants were poor inducers of Hspa1a, and reduced levels of Hspa8 mRNA and protein, indicating multiple compromises in chaperoning capacity. To promote HSP expression, cultures were treated with the putative HSP coinducer, arimoclomol, and class I histone deacetylase inhibitors, to promote active chromatin for transcription, and with the combination. Treatments had variable, often different effects on the expression of Hspa1a and Hspa8, depending on the ALS variant expressed, mRNA distribution (somata and dendrites), and biomarker of toxicity measured (histone acetylation, maintaining nuclear TDP-43 and the neuronal Brm/Brg-associated factor chromatin remodeling complex component Brg1, mitochondrial transport, FUS aggregation). Overall, histone deacetylase inhibition alone was effective on more measures than arimoclomol. As in the FUS model, arimoclomol failed to induce HSPA1A or preserve Hspa8 mRNA in the TDP-43 model, despite preserving nuclear TDP-43 and Brg1, indicating neuroprotective properties other than HSP induction. The data speak to the complexity of drug mechanisms against multiple biomarkers of ALS pathogenesis, as well as to the importance of HSPA8 for neuronal proteostasis in both somata and dendrites.
摘要：
蛋白质错误折叠和错误定位是神经退行性疾病的常见主题，包括运动神经元疾病，肌萎缩侧索硬化（ALS）。维持蛋白质稳定是一个交叉的治疗目标，包括上调热休克蛋白（HSP）以增加伴侣能力。运动神经元对上调应激诱导的HSPA1A有很高的阈值，但组成性表达高水平的HSPA8。这项研究比较了这些HSP在培养的运动神经元中的表达，这些运动神经元表达与家族性ALS相关的三种变体：TDP-43G348C，FUSR521G或SOD1G93A。所有变体都是Hspa1a的不良诱导剂，Hspa8mRNA和蛋白水平降低，表明陪伴能力有多重妥协。为了促进HSP表达，用推定的HSP共诱导剂处理培养物，Arimoclomol,I类组蛋白去乙酰化酶（HDAC）抑制剂促进活性染色质转录，和组合。治疗有变化，通常对Hspa1a和Hspa8的表达有不同的影响，取决于所表达的ALS变体，mRNA分布（躯体和树突），和测量的毒性生物标志物(组蛋白乙酰化，维持核TDP-43和nBAF染色质重塑复合物组分Brg1，线粒体运输，FUS聚合)。总的来说,单独的HDAC抑制比阿利莫罗更有效。和FUS模型一样,在TDP-43模型中，Arimoclomol未能诱导HSPA1A或保留Hspa8mRNA，尽管保留了核TDP-43和Brg1，表明除HSP诱导外的神经保护特性。数据说明了针对ALS发病机理的多种生物标志物的药物机制的复杂性，以及HSPA8对躯体和树突中神经元蛋白稳定的重要性。
