Pharmacological induction of heat-shock proteins alleviates polyglutamine-mediated motor neuron disease
Pharmacological induction of heat-shock proteins alleviates polyglutamine-mediated motor neuron disease
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DOI：
10.1073/pnas.0506249102
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发表时间：
2005-11-15
影响因子：
11.1
通讯作者：
Sobue, G
中科院分区：
文献类型：
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作者：
Katsuno, M;Sang, C;Sobue, G
脊髓和延髓性肌萎缩症 (SBMA) 是一种成人发病的运动神经元疾病，由雄激素受体基因 (AR) 第一个外显子中编码多聚谷氨酰胺束的三核苷酸 CAG 重复序列扩增引起。致病性多聚谷氨酰胺扩增的 AR 蛋白以配体依赖性方式在细胞核中积累，并通过干扰转录因子和共激活因子来抑制转录。热休克蛋白 (HSP) 是应激诱导的分子伴侣，可促进异常蛋白质的重折叠和降解。香叶基香叶丙酮 (GGA) 是一种无毒抗溃疡药物，已被证明可有效诱导包括中枢神经系统在内的各种组织中的 HSP 表达。在 SBMA 细胞模型中，GGA 增加 Hsp70、Hsp90 和 Hsp105 的水平，并抑制细胞死亡和致病性 AR 的积累。口服 GGA 还可上调 SBMA 转基因小鼠中枢神经系统中 HSP 的表达，并抑制致病性 AIR 蛋白的核积累，从而改善多谷氨酰胺依赖性神经肌肉表型。这些观察结果表明，虽然临床效果似乎需要高剂量，但口服 GGA 给药是治疗多谷氨酰胺介导的神经退行性疾病（包括 SBMA）的安全且有前景的候选药物。
Spinal and bulbar muscular atrophy (SBMA) is an adult-onset motor neuron disease caused by the expansion of a trinucleotide CAG repeat encoding the polyglutamine tract in the first exon of the androgen receptor gene (AR). The pathogenic, polyglutamine-expanded AR protein accumulates in the cell nucleus in a ligand-dependent manner and inhibits transcription by interfering with transcriptional factors and coactivators. Heat-shock proteins (HSPs) are stress-induced chaperones that facilitate the refolding and, thus, the degradation of abnormal proteins. Geranylgeranylacetone (GGA), a nontoxic antiulcer drug, has been shown to potently induce HSP expression in various tissues, including the central nervous system. In a cell model of SBMA, GGA increased the levels of Hsp70, Hsp90, and Hsp105 and inhibited cell death and the accumulation of pathogenic AR. Oral administration of GGA also up-regulated the expression of HSPs in the central nervous system of SBMA-transgenic mice and suppressed nuclear accumulation of the pathogenic AIR protein, resulting in amelioration of polyglutamine-dependent neuromuscular phenotypes. These observations suggest that, although a high dose appears to be needed for clinical effects, oral GGA administration is a safe and promising therapeutic candidate for polyglutamine-mediated neurodegenerative diseases, including SBMA.