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 (PrP^C). Extracellular STI1 can prevent Aβ toxic signaling by (i) interfering with Aβ binding to PrP^C 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.

Keywords: ALS; Alzheimer's disease; HOP; Huntington's disease; Parkinson's disease; STIP1; TDP-43; tau.

Figure 1

Schematic of the ATPase cycle of Hsp90. Hsp90 homodimer initially adopts an open V-shaped conformation. Binding of ATP to the N-terminal ATPase domain induces a conformational change where the N-terminal lids close and ATP is cradled in the nucleotide-binding pocket. This induces dimerization of the N-terminal domains of each homodimer followed by closure of Hsp90 and recruitment of the M domain for ATP hydrolysis. The dimers dissociate into a semi-open intermediate state with ADP bound. Release of ADP dissociates the N-termini to allow repetition of the ATPase cycle. Common Hsp90 inhibitors (geldanamycin, radicicol, and purine derivatives) bind to the N-terminus of Hsp90 and compete with ATP for binding.

Figure 2

Outline of the chaperone response in protein folding. Chaperones facilitate proper folding of a diverse array of client proteins and prevent oligomer and aggregate formation. If folding is not possible, misfolded proteins are targeted for protein degradation to maintain proper protein homeostasis. Degradation is achieved through the ubiquitin-proteasome system (UPS) or the autophagy-lysosome pathway. A list of diseases and the associated aggregate discussed in this review are outlined.

Figure 3

Domain structure of STI1 and sites of post-translational modifications (PTM). STI1 is composed of three structurally similar tetratricopeptide repeat domains (TPR1, TPR2A, and TPR2B) and two regions rich in aspartate and proline residues (DP1 and DP2). The protein is subject to phosphorylation (S16, S189, T198, Y354, and S481). CK2 phosphorylation at S189 induces STI1 accumulation in the nucleus. In contrast phosphorylation by cdc2 at T198 localizes STI1 to the cytoplasm. Five possible SUMOylation sites have been identified (K123, K210, K312, K395, and K486). SUMOylation by PIAS1 at K210 may stimulate SUMOylation at the alternate sites. Association of PIAS1 with STI1 by a SUMO-independent mechanism increases STI1 nuclear accumulation. Regions that bind HSP70, HSP90, and PrP^C are illustrated.

Figure 4

STI1 signaling mediated by the cellular prion protein (PrP^C). (Right) PrP^C binding to extracellular STI1 induces neuroprotective and neuro- differentiation through Ca²⁺ influx via α7-nAChR. (Left) Aβ oligomers transmit toxic signaling events through PrP^C. STI1 inhibits Aβ oligomer binding to PrP^C and/or activate protective signaling events.