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.

Differential Proteomic Analysis of Astrocytes and Astrocytes-Derived Extracellular Vesicles from Control and Rai Knockout Mice: Insights into the Mechanisms of Neuroprotection

“…The characterization of the proteomes of both astrocytes and ADEVs suggests that the differentially abundant proteins cooperate in specific molecular pathways, such as the HIF-1α transcriptional pathway, the unfolding protein response, cellular energetic metabolism, the proteasome-ubiquitin system, cell adhesion-cell motility, and oxidative stress. Among the differentially expressed proteins, two of these, namely ENOA and HSP7C, a member of the HSP70 family, attracted our attention because of the involvement of ENOA in the regulation of ECM degradation, ROS and NO production [ 20 ], and the ability of HSP70 to modulate cytokine-dependent NF-κB activation and NO production in astrocytes [ 21 , 22 ]. Control and Rai −/− astrocytes were treated for 24 h with IL-17 or left untreated, and HSP70 and ENOA protein levels were analyzed by immunoblot.…”

Microdissected Pyramidal Cell Proteomics of Alzheimer Brain Reveals Alterations in Creatine Kinase B-Type, 14-3-3-γ, and Heat Shock Cognate 71

“…There was also some neuropil positivity which appeared to stem from glial cells. Since the Hsp70 protein family is stress-activated neuroprotectors, it is reasonable to assume that upregulated Hsc71 is a compensatory mechanism to cellular stress in AD neurons (Kim et al, 2020). Other members of the Hsp70 family have been shown to accumulate extracellularly, but Hsc71 seems to be an exception since this chaperone was specifically accumulated intracellularly in AD hippocampal neurons.…”

Neural functions of small heat shock proteins

“…allows them to take part in neurotransmission regulation and neuronal protection (Bechtold and Brown, 2000). Moreover, HSP70 provokes a neuroprotective effect and increases neuronal survival under heat shock, oxidative stress, and ischemia-like conditions in vitro and in vivo models (Yenari et al, 1999;Kim et al, 2020). It has been proposed that glial cells can transfer HSP70 protein to neurons and promotes neuronal stress tolerance as a neuroprotective mechanism (Guzhova et al, 2001).…”