Molecular chaperones and regulation of tau quality control: strategies for drug discovery in tauopathies

Abstract

Tau is a microtubule-associated protein that accumulates in at least 15 different neurodegenerative disorders, which are collectively referred to as tauopathies. In these diseases, tau is often hyperphosphorylated and found in aggregates, including paired helical filaments, neurofibrillary tangles and other abnormal oligomers. Tau aggregates are associated with neuron loss and cognitive decline, which suggests that this protein can somehow evade normal quality control allowing it to aberrantly accumulate and become proteotoxic. Consistent with this idea, recent studies have shown that molecular chaperones, such as heat shock protein 70 and heat shock protein 90, counteract tau accumulation and neurodegeneration in disease models. These molecular chaperones are major components of the protein quality control systems and they are specifically involved in the decision to retain or degrade many proteins, including tau and its modified variants. Thus, one potential way to treat tauopathies might be to either accelerate interactions of abnormal tau with these quality control factors or tip the balance of triage towards tau degradation. In this review, we summarize recent findings and suggest models for therapeutic intervention.

Figure 1. Hsp70, Hsp90 and the chemical structures of select inhibitors

Hsp: Heat shock protein.

Figure 2. Model of heat shock protein 70–heat shock protein 90 cycling

Unfolded or misfolded substrates enter the chaperone cycle by engaging in interactions with J-proteins, which recruit Hsp70 family chaperones. The ATPase cycle of Hsp70 can result in substrate folding, triage through the proteasome or ‘hand-off’ to the Hsp90 system. The ATPase cycle of Hsp90 refines folding and stabilizes the active form of many kinases and transcription factors. In addition, the Hsp90 cycle makes triage decisions, through CHIP-mediated ubiquitination and degradation. CHIP: C-terminal Hsp70 interacting protein; HOP: Hsp70/Hsp90 organizing protein; Hsp: Heat shock protein; NEF: Nucleotide exchange factor; PPIase: Peptidyl-prolyl cis-trans isomerase.

Figure 3. Overview of tau quality control by molecular chaperones

From the microtubule-bound pool, tau might be released in a form that is capable of re-binding microtubule (termed ‘cycling tau’). Alternatively, hyperphosphorylated and aggregation-prone tau might accumulate. Chaperones are involved in all stages of cycling tau, in mediating phosphorylation and in making triage decisions. BAG: Bcl2-associated anthanogene; CHIP: C-terminal Hsp70 interacting protein; FKBP51: FK506-binding protein 51 kDa; Hsp: Heat shock protein.