Impact of Heat Shock Proteins in Neurodegeneration: Possible Therapeutical Targets

Abstract

Human neurodegenerative diseases occur as a result of various factors. Regardless of the variety in the etiology of development, many of these diseases are characterized by the accumulation of pathological, misfolded proteins; hence, such diseases are considered as proteinopathies. While plenty of research study has been conducted in order to identify the pathophysiology of these proteinopathies, there is still a lack of understanding in terms of potential therapeutic targets. Molecular chaperones present the main workforce for cellular protection and stress response. Therefore, considering these functions, molecular chaperones present a promising target for research within the field of conformational diseases that arise from proteinopathies. Since the association between neurodegenerative disorders and their long-term consequences is well documented, the need for the development of new therapeutic strategies becomes even more critical. In this review, we summarized the molecular function of heat shock proteins and recent progress on their role, involvement, and other mechanisms related to neurodegeneration caused by different etiological factors. Based on the relevant scientific data, we will highlight the functional classification of heat shock proteins, regulatin, and their therapeutic potential for neurodegenerative disorders.

Profiling the Hsp70 Chaperone Network in Heat-Induced Proteotoxic Stress Models of Human Neurons

“…Considering the functional significance of these Hsp70 chaperones in the proteotoxic stress response, their targeting to reverse and combat protein aggregation-mediated neurodegeneration is potentially an excellent therapeutic approach. Hsp70 up-regulation and modulation are widely tested in treating many neurodegenerative diseases [ 18 , 19 , 56 , 57 ]. Chaperones, in combination, are more potent in eliciting preventive responses than individual entities [ 58 ].…”

Heat shock proteins: Biological functions, pathological roles, and therapeutic opportunities

“…HSPs have recently become a focus of research in neurodegenerative diseases (such as AD, Parkinson's disease, polyglutamine (polyQ) disease, Amyotrophic lateral sclerosis, Huntington's, and many others) because the pathogenesis of these diseases is highlighted by the intracellular proteins aberrant folding and inclusion body formation. 282 HSPs serve as protein‐folding machinery and work together with UPS to assist in removing aberrant proteins, exert antiapoptotic effects, and maintain the dynamic homeostasis of dopaminergic neurons against stress conditions such as oxidative damage. Dysfunction of HSPs, including HSP90, HSP70, and HSP27, may contribute to the pathogenesis of Parkinson's disease as a study showed, suggesting that HSPs may come to be potential therapeutic targets for neurodegenerative disorders such as PD.…”

“…355 Moreover, many studies shown that HSP70 may solubilize α-syn and promote the degradation of its insoluble forms via chaperone-mediated autophagy and the proteasome pathway in PD. 281,282 In addition, other studies suggested that HSP70 plays a role in neuroprotective in diseases that affect CNS and showed promising outcome in reducing the loss of neuron cells. 356 Therefore, future strategies for developing treatments for neurodegenerative diseases through targeting HSP70 can be proposed.…”

“…Recently, studies showed that during the exercise, the released extracellular HSPs 70 (eHSP70) can be internalized by the motoneurons, and then act as intracellular chaperons, protecting cells against protein denaturation, whereas reduced expression of inducible HSP 70 (iHSP70) is associated with neurodegenerative diseases, stressing the importance of understanding the physiological function of extracellular HSP70 in the treatment of neurodegenerative and other neuronal diseases 355 . Moreover, many studies shown that HSP70 may solubilize α‐syn and promote the degradation of its insoluble forms via chaperone‐mediated autophagy and the proteasome pathway in PD 281,282 . In addition, other studies suggested that HSP70 plays a role in neuroprotective in diseases that affect CNS and showed promising outcome in reducing the loss of neuron cells 356 .…”

Protein Interactome of Amyloid-β as a Therapeutic Target

“…In general, the ability of the chaperone machine to bind Aβ and prevent the formation of amyloid aggregates and their toxicity in vitro is well-established [ 102 , 103 ], but experimental confirmation of this hypothesis in vivo has not yet been presented.…”