Tonkiss J, Calderwood S K
Center for Behavioral Development, Boston University School of Medicine, Boston, MA, USA.
Int J Hyperthermia. 2005 Aug;21(5):433-44. doi: 10.1080/02656730500165514.
The heat shock protein (HSP) molecular chaperones are the primary cellular defense against damage to the proteome, initiating refolding of denatured proteins and regulating degradation after severe protein damage. Many neurodegenerative disorders involve aberrant protein folding and protein damage, which accumulates in an age-dependent manner. Ageing is associated with the decrease in activity of the heat shock transcription factors (HSF) that regulate HSP gene transcription. Neuronal cells seem particularly vulnerable in this sense as HSF activity and HSP expression are relatively weak in such cells and motor neurons appear to require input of HSP secreted from adjacent glial cells to maintain adequate molecular chaperone levels. It may be significant that motor neurons have been shown to be the sensitive cells in the ageing of Drosophila and C. elegans and that these organisms may acquire extended lifespans with over-expression of small heat shock proteins and HSF1. HSF1 transcriptional activity has been discussed in neuronal cells, concentrating on the regulation and activity of HSF1 and HSF2 and their role in HSP expression, during neurodegenerative diseases and as mediators of cell survival.
热休克蛋白（HSP）分子伴侣是细胞对抗蛋白质组损伤的主要防御机制，可启动变性蛋白的重新折叠，并在蛋白质严重损伤后调节其降解。许多神经退行性疾病都涉及异常的蛋白质折叠和蛋白质损伤，且这些损伤会以年龄依赖性方式累积。衰老与调节HSP基因转录的热休克转录因子（HSF）活性降低有关。从这个意义上讲，神经元细胞似乎特别脆弱，因为此类细胞中的HSF活性和HSP表达相对较弱，而且运动神经元似乎需要相邻胶质细胞分泌的HSP输入，以维持足够的分子伴侣水平。有研究表明运动神经元是果蝇和秀丽隐杆线虫衰老过程中的敏感细胞，并且这些生物体可能通过过表达小热休克蛋白和HSF1来延长寿命，这一点可能具有重要意义。在神经退行性疾病期间以及作为细胞存活的介质，人们已经在神经元细胞中讨论了HSF1的转录活性，重点关注HSF1和HSF2的调节与活性及其在HSP表达中的作用。
