Heat shock proteins and protection of the nervous system
Heat shock proteins and protection of the nervous system
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DOI：
10.1196/annals.1391.032
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发表时间：
2007-01-01
期刊：
影响因子：
--
通讯作者：
Brown, Ian R.
中科院分区：
文献类型：
--
作者：
Brown, Ian R.
对细胞应激反应的操纵为保护脑细胞免受缺血和神经退行性疾病的损害提供了策略。热休克蛋白70的过表达减少了哺乳动物脑中的缺血性损伤。对HSP70中提供缺血神经保护的结构域的研究揭示了羧基末端结构域的重要性。热休克蛋白的共同诱导剂Arimoclomol在脊髓和运动皮层运动神经元退化的小鼠模型中延缓了肌萎缩侧索硬化症(ALS)的进展。雷公藤红素是一种很有前途的神经退行性疾病的候选药物，它可以诱导组织培养中分化的神经元表达一系列热休克蛋白。热休克预适应在突触功能水平保护神经系统，选择性过表达HSP70增强突触保护水平。高温后，在大脑富含突触的区域，结构性表达的Hsc70增加，在那里它与Hsp40结合形成一个可以重新降解变性蛋白的复合体。神经元对应激的耐受并不完全依赖于其自身的热休克蛋白，而是可以由邻近神经胶质细胞的热休克蛋白来补充。因此，在神经损伤部位应用外源性HSPs是维持神经元存活的有效策略。
Manipulation of the cellular stress response offers strategies to protect brain cells from damage induced by ischemia and neurodegenerative diseases. Overexpression of Hsp70 reduced ischemic injury in the mammalian brain. Investigation of the domains within Hsp70 that confers ischemic neuroprotection revealed the importance of the carboxyl-terminal domain. Arimoclomol, a coinducer of heat shock proteins, delayed progression of amyotrophic lateral sclerosis (ALS) in a mouse model in which motor neurons in the spinal cord and motor cortex degenerate. Celastrol, a promising candidate as an agent to counter neurodegenerative diseases, induced expression of a set of Hsps in differentiated neurons grown in tissue culture. Heat shock "preconditioning" protected the nervous system at the functional level of the synapse and selective overexpression of Hsp70 enhanced the level of synaptic protection. Following hyperthermia, constitutively expressed Hsc70 increased in synapse-rich areas of the brain where it associates with Hsp40 to form a complex that can retold denatured proteins. Stress tolerance in neurons is not solely dependent on their own Hsps but can be supplemented by Hsps from adjacent glial cells. Hence, application of exogenous Hsps at neural injury sites is an effective strategy to maintain neuronal viability.