Stress genes protect brain

The article in this issue by Yenari and colleagues reports an exciting result. Brain injections of a defective herpes virus containing the HSP70 heat shock gene improves the survival of neurons in striatum following ischemia and improves the survival of hippocampal dentate gyrus neurons following status epilepticus. Although this is an animal study, these data suggest a novel approach for treatment of ischemia, status epilepticus, trauma, and degenerative disorders. The use of heat shock genes for treatment has the unique potential for protecting against a wide variety of injuries because the stress gene response is not disease specific. ’,2 The role of HSP70 has been confusing to many because it is induced following cell and yet HSP70 confers resistance against most types of injury once it is i n d ~ c e d . ~ Understanding some of the mechanisms of induction and the functions of the inducible heat shock proteins will help explain this apparent paradox. In the era of the greenhouse effect and global warming, it is interesting that the large family of heat shock genes is not better known in the neurology and neuroscience communities. The prototypic heat shock gene is HSP70 (called HSP72 in the article by Yenari and colleagues), which is present at low levels in normal brain and is highly induced by many types of injury, including heat, heavy metals, and ischemia. ‘ It is believed that the presence of denatured proteins within cells stimulates proteins called heat shock factors (HSFs) that bind to each other and then to the hp70 gene to trigger its t r a n s c r i p t i ~ n . ~ , ~ ~ ~ Once the HSP70 protein is synthesized, it binds via an adenosine triphosphate (ATE’)-dependent process to the denatured proteins within cells to prevent further denaturation and to promote renaturation of proteins. In vitro experiments demonstrate that HSP70 protein, other HSPs, and ATP, when added to partially denatured proteins that exhibit no enzymatic activity, can restore enzymatic activity. Hence, the presence of denatured proteins serves as a stimulus for HSP70 induction, but once HSP7O is induced it helps to restore the tertiary structure of the proteins and to restore their enzymatic activity. ”-’* Once HSP70 is present in the cell, HSP70 partially protects against subsequent lethal stimuli as long as the injury occurs during the period of HSP70 expression and the injury is not overwhelming. Other heat shock protein family members generally function as “chaperones” that assist in proper folding of proteins, unfolding of abnormal proteins, or the chaperoning of proteins across cell or organelle memb rane~ . ’~ . ’~ They can even participate in the folding of abnormal proteins such as prions. Examples of protein chaperones include the constitutive hsc70 heat shock gene that binds to all newly forming proteins to ensure proper folding of the mature protein.16 Hsp60 and grp75 chaperone proteins into mitochondria, ”,” and grp78 chaperones proteins through the endoplasmic reticulum. ’’ Hsp90 binds to hp70 and the glucocorticoid receptor and thereby regulates their funct iom3 Many studies have documented that heat, toxins, seizures, trauma, and ischemia induce the HSP70 mRNA and protein in brain.2,20-25 Although one stimulus for HSP70 induction is believed to be the presence of denatured proteins within the cells, calcium and other second messengers have also been implicated in HSP70 induction.2 Following focal infarction, hsp70 mRNA can be induced throughout the region of ischemia. HSP70 protein, however, is induced only in vascular cells within the infarction. Outside the area of infarction HSP70 protein is expressed in neurons. We have proposed that this region of neuronal HSP70 expression outside the infarction represents the area of protein denaturation. This region of protein denaturation can be viewed as a “penumbra” that may extend only short distances away from an infarct or that may include the entire middle cerebral artery distribution if the ischemia is moderate and does not produce infarction. This protein denaturation penumbra27 is only one of many that can be defined on the basis blood flow, glucose metabolism, and electrophysiology as well as other parameters.28p30 These results, combined with evidence of HSP70 induction following toxin exposure and seizures, have led investigators to suggest that HSP70 mRNA and protein expression can be used to delineate regions of injury that are not infarcted.22 In fact, if the magnetic resonance imaging methods that are used to detect changes in protein conformation in vitro could be used to detect changes of protein conformation in vivo, it might be possible to image protein denaturation in humans following brief cerebral ischemia or any other cell-damaging, protein-denaturing disease. Most importantly, the current study points to the treatment potential of heat shock proteins. Previous studies show that mild heat shock protects neurons against the excitotoxin g l ~ t a m a t e ~ ’ , ~ ~ and glia against lethal heat shock and acidosis.33 Transfection of glia with hp70 protects the glia against heat glucose d e p r i ~ a t i o n , ~ ~ and combined glucose and oxygen depri~ation. ~‘ Similarly, transfection of neurons with 26 ~ __________ _______