Heat Shock Protein 70 (HSP70) Induction: Chaperonotherapy for Neuroprotection after Brain Injury

Abstract

The 70 kDa heat shock protein (HSP70) is a stress-inducible protein that has been shown to protect the brain from various nervous system injuries. It allows cells to withstand potentially lethal insults through its chaperone functions. Its chaperone properties can assist in protein folding and prevent protein aggregation following several of these insults. Although its neuroprotective properties have been largely attributed to its chaperone functions, HSP70 may interact directly with proteins involved in cell death and inflammatory pathways following injury. Through the use of mutant animal models, gene transfer, or heat stress, a number of studies have now reported positive outcomes of HSP70 induction. However, these approaches are not practical for clinical translation. Thus, pharmaceutical compounds that can induce HSP70, mostly by inhibiting HSP90, have been investigated as potential therapies to mitigate neurological disease and lead to neuroprotection. This review summarizes the neuroprotective mechanisms of HSP70 and discusses potential ways in which this endogenous therapeutic molecule could be practically induced by pharmacological means to ultimately improve neurological outcomes in acute neurological disease.

Keywords: brain injury; chaperone neuroprotection; heat shock protein 70; pharmacological induction.

Figure 1

HSP70 chaperone machinery. HOP and CHIP compete for HSP70’s C-terminus during protein folding and degradation, while HIP and Bag-1 compete for the ATPase domain. Depending on the site of HIP or Bag-1 binding, HSP70 may lead to protein folding (HIP/HOP pathway; (A) or to protein degradation through the proteasome (CHIP/Bag-1 pathway; (B). Ub = ubiquitin.

Figure 2

Brain injury induces apoptotic cell death by distinct pathways. The intrinsic pathway is centered around signals emanating from the mitochondria, whereas the extrinsic or receptor-mediated pathway begins when death receptors bind to their ligands. The prototypical death receptor Fas is shown here. HSP70 and HSP27 have been shown to interfere with apoptosis as indicated in the figure. See text for more details. (FasL = Fas ligand; AIF = apoptosis inducing factor; Akt = protein kinase B; Apaf-1 = apoptosis protease activating factor-1; Cyt C = cytochrome c; JNK = c-Jun N-terminal kinase; Dyn = dynamin).

Figure 3

Influence of HSPs in innate immunity. Following ischemic stroke, HSPs have been shown to inhibit the activation of the transcription factor NF-kB and to prevent its nuclear translocation. Acute brain insults (brain injury) trigger activation of NF-kB by causing the phosphorylation and degradation of its inhibitor protein IkB, which normally keeps NF-kB (which consists of the heterodimers p65 and p50) tethered to the cytosol. Once NF-kB is able to translocate to the nucleus, it binds to promoter regions of several pro-inflammatory genes and leads to an inflammatory response.