The Hsp70/Hsp90 Chaperone Machinery in Neurodegenerative Diseases

Abstract

The accumulation of misfolded proteins in the human brain is one of the critical features of many neurodegenerative diseases, including Alzheimer's disease (AD). Assembles of beta-amyloid (Aβ) peptide—either soluble (oligomers) or insoluble (plaques) and of tau protein, which form neurofibrillary tangles, are the major hallmarks of AD. Chaperones and co-chaperones regulate protein folding and client maturation, but they also target misfolded or aggregated proteins for refolding or for degradation, mostly by the proteasome. They form an important line of defense against misfolded proteins and are part of the cellular quality control system. The heat shock protein (Hsp) family, particularly Hsp70 and Hsp90, plays a major part in this process and it is well-known to regulate protein misfolding in a variety of diseases, including tau levels and toxicity in AD. However, the role of Hsp90 in regulating protein misfolding is not yet fully understood. For example, knockdown of Hsp90 and its co-chaperones in a Caenorhabditis elegans model of Aβ misfolding leads to increased toxicity. On the other hand, the use of Hsp90 inhibitors in AD mouse models reduces Aβ toxicity, and normalizes synaptic function. Stress-inducible phosphoprotein 1 (STI1), an intracellular co-chaperone, mediates the transfer of clients from Hsp70 to Hsp90. Importantly, STI1 has been shown to regulate aggregation of amyloid-like proteins in yeast. In addition to its intracellular function, STI1 can be secreted by diverse cell types, including astrocytes and microglia and function as a neurotrophic ligand by triggering signaling via the cellular prion protein (PrPC). Extracellular STI1 can prevent Aβ toxic signaling by (i) interfering with Aβ binding to PrPC and (ii) triggering pro-survival signaling cascades. Interestingly, decreased levels of STI1 in C. elegans can also increase toxicity in an amyloid model. In this review, we will discuss the role of intracellular and extracellular STI1 and the Hsp70/Hsp90 chaperone network in mechanisms underlying protein misfolding in neurodegenerative diseases, with particular focus on AD.

Genistein Modifies Hamster Behavior and Expression of Inflammatory Factors following Subchronic Unpredictable Mild Stress

“…Even variations of Hsp70 appear to be correlated with regulatory cell growth and differentiation processes following neurodegenerative states [38]. Indeed, an upregulation of Hsp70 detected in stressed hamsters fed with genistein tends to further underlie its protective measures in a similar fashion to that of other anti-apoptotic plus antidepressant compounds [39], and this is in line with its upregulatory trend reported during traumatic brain injuries [40] and during ischemic episodes [33].…”

Curcumin Protects an SH-SY5Y Cell Model of Parkinson’s Disease Against Toxic Injury by Regulating HSP90

“…The HSP family plays a major role in activating against protein misfolding in diseases including PD [21]. As reviewed by Lackie et al, early observation of Hsp90, Hsp70, Hsp60, Hsp40, and Hsp27 has provided a deeper insight into these chaperones [21]. For instance, Hsp60 was found to intervene in PD pathogenesis in 6-OHDA-lesioned rat models [22].…”

“…For instance, Hsp60 was found to intervene in PD pathogenesis in 6-OHDA-lesioned rat models [22]. Hsp70 overexpression was reported to prevent α-synuclein accumulation and to reverse dopaminergic neuron loss [21]. Falsone et al revealed that Hsp90 blocked α-synuclein aggregation in an in vitro model [23].…”

Uncaria rhynchophylla Ameliorates Parkinson’s Disease by Inhibiting HSP90 Expression: Insights from Quantitative Proteomics

“…In addition, HSP90 could regulate the proliferative and senescent client proteins [14], including PI3K, AKT, MAPKs, CDK4, Cyclin D1, and VEGF, which also indicated that HSP90 played an important role in the PD [24,25,38,39]. Quantitative proteomics technique is a reliable and precise method to predict the disease-specific targets and underlying mechanism [21].…”

“…S2 and Table S3). Previous studies have indicated that HSP90 plays an important role in the anti-PD field [22][23][24], therefore, HSP90AA1 and HSP90AB1 were speculated to be two critical proteins affected by URE treatment in MPP + -induced SH-SY5Y cells. HSP90, as a molecular chaperone, played an indispensable role in normal cellular homeostasis by regulating the folding, stability, and function of its client proteins, some of which have effects in regulating signal transduction pathways.…”