Abstract：
Protein misfolding and mislocalization are common to both familial and sporadic forms of amyotrophic lateral sclerosis (ALS). Maintaining proteostasis through induction of heat shock proteins (HSP) to increase chaperoning capacity is a rational therapeutic strategy in the treatment of ALS. However, the threshold for upregulating stress-inducible HSPs remains high in neurons, presenting a therapeutic obstacle. This study used mouse models expressing the ALS variants FUSR521G or SOD1G93A to follow up on previous work in cultured motor neurons showing varied effects of the HSP co-inducer, arimoclomol, and class I histone deacetylase (HDAC) inhibitors on HSP expression depending on the ALS variant being expressed. As in cultured neurons, neither expression of the transgene nor drug treatments induced expression of HSPs in cortex, spinal cord or muscle of FUSR521G mice, indicating suppression of the heat shock response. Nonetheless, arimoclomol, and RGFP963, restored performance on cognitive tests and improved cortical dendritic spine densities. In SOD1G93A mice, multiple HSPs were upregulated in hindlimb skeletal muscle, but not in lumbar spinal cord with the exception of HSPB1 associated with astrocytosis. Drug treatments improved contractile force but reduced the increase in HSPs in muscle rather than facilitating their expression. The data point to mechanisms other than amplification of the heat shock response underlying recovery of cognitive function in ALS-FUS mice by arimoclomol and class I HDAC inhibition and suggest potential benefits in counteracting cognitive impairment in ALS, frontotemporal dementia and related disorders.
摘要：
蛋白质错误折叠和错误定位在家族性和偶发性肌萎缩性侧索硬化症（ALS）中很常见。通过诱导热休克蛋白（HSP）以增加伴侣能力来维持蛋白质平衡是治疗ALS的合理治疗策略。然而,上调应激诱导HSP的阈值在神经元中仍然很高，提供治疗障碍。这项研究使用表达ALS变体FUSR521G或SOD1G93A的小鼠模型来跟踪先前在培养的运动神经元中的工作，显示HSP共诱导剂的不同作用，Arimoclomol,和I类组蛋白脱乙酰酶(HDAC)抑制剂对HSP表达的影响取决于所表达的ALS变体。就像培养的神经元一样，无论是转基因的表达还是药物治疗都不诱导皮质中HSPs的表达，FUSR521G小鼠的脊髓或肌肉，表示热休克反应的抑制。尽管如此，Arimoclomol,和RGFP963，恢复了认知测试的表现，并改善了皮质树突脊柱密度。在SOD1G93A小鼠中，多个HSP在后肢骨骼肌中上调，但腰脊髓中没有，HSPB1与星形细胞增多相关。药物治疗改善了收缩力，但减少了肌肉中HSP的增加，而不是促进其表达。数据表明，除了通过Arimoclomol和I类HDAC抑制ALS-FUS小鼠认知功能恢复的热休克反应的放大之外，还表明了对抗ALS认知障碍的潜在益处。额颞叶痴呆和相关疾病。
