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

Jong Youl Kim,Joohyun Park,Midori A Yenari,Jong Eun Lee,Sumit Barua,Mei Ying Huang

doi:10.3390/cells9092020

Jong Youl Kim, Joohyun Park + Show 4 more

Open Access

https://doi.org/10.3390/cells9092020

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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.

Highlights

After various insults to the brain, a coordinated stress response which seems to protect it from further injury occurs
Dissociated heat shock factors (HSFs) migrate to the nucleus of the stressed cell, where they become phosphorylated, often by a protein such as kinase C. This process forms activated trimers that bind to the heat shock elements (HSEs), which is a highly conserved regulatory sequence located on the heat shock gene
HSP70 interfered with cytochrome c release [43,60] and inhibited apoptosis inducing factor (AIF) translocation to the nucleus [61] while reducing ischemic brain injury

Summary

Introduction

After various insults to the brain, a coordinated stress response which seems to protect it from further injury occurs. HSP70 induction represents an endogenous protective mechanism that occurs in the penumbra of the hippocampus, but not of other core areas, in the ischemic stroke model [3,4]. More than two decades of research involving such models have shown that HSP70 has the ability to protect against multiple types of cell death, including apoptosis and necrosis. HSP70 modulates inflammatory pathways and, appears to improve neurological outcomes through interrupting both cell death and immune responses [7]. It should be noted, that these studies possessed limited translational utility because they relied upon either genetic mutant models or gene transfer models, and upon heat stress to induce HSP70 overexpression. We discuss the mechanisms of HSP70 neuroprotection in brain injury (ischemic stroke and traumatic brain injury (TBI)), along with pharmacological HSP70 inducers and their possible applications at the clinical level

Classification and Functional Role of Heat Shock Protein 70

Role of Heat Shock Protein 70 in Brain Injury

Inflammation Regulation of Heat Shock Protein 70

Conclusions