Targeting Hsp90/Hsp70-based protein quality control for treatment of adult onset neurodegenerative diseases

Abstract

Currently available therapies for adult onset neurodegenerative diseases provide symptomatic relief but do not modify disease progression. Here we explore a new neuroprotective approach based on drugs targeting chaperone-directed protein quality control. Critical target proteins that unfold and aggregate in these diseases, such as the polyglutamine androgen receptor in spinal and bulbar muscular atrophy, huntingtin in Huntington's disease, α-synuclein in Parkinson's disease, and tau in Alzheimer's disease, are client proteins of heat shock protein 90 (Hsp90), and their turnover is regulated by the protein quality control function of the Hsp90/Hsp70-based chaperone machinery. Hsp90 and Hsp70 have opposing effects on client protein stability in protein quality control; Hsp90 stabilizes the clients and inhibits their ubiquitination, whereas Hsp70 promotes ubiquitination dependent on CHIP (C terminus of Hsc70-interacting protein) and proteasomal degradation. We discuss how drugs that modulate proteostasis by inhibiting Hsp90 function or promoting Hsp70 function enhance the degradation of the critical aggregating proteins and ameliorate toxic symptoms in cell and animal disease models.

Keywords: CHIP; neurodegeneration; proteasome; protein aggregation; ubiquitination.

Figure 1. Mechanism of ligand binding cleft opening and AR-Hsp90-immunophilin heterocomplex assembly

The ATP-dependent conformation of Hsp70 binds initially to the AR (polyQ AR), and in an ATP-, K⁺-, and Hsp40-dependent step, an AR-Hsp70 complex is formed that is primed to interact with Hsp90. After Hsp90 binding, there is a second ATP- and K⁺-dependent step that is rate limiting and leads to opening of the steroid binding cleft, enabling access of the steroid (indicated by the steroid structure). K⁺ is required for Hsp70 ATPase activity, implying active participation of Hsp70 in both steps of cleft opening. During receptor-Hsp90 heterocomplex assembly in cells and cell lysates, Hop (Hsp organizing protein) and some of the Hsp70 dissociate during or at the end of the cleft opening step. The dashed line for Hsp70 indicates it is present in amounts that are substoichiometric with respect to the receptor at this step. The receptor-bound Hsp90 is now in its ATP-dependent conformation and can be bound by p23, which stabilizes the chaperone in that conformation, preventing disassembly of the receptor-Hsp90 heterocomplex. When Hop dissociates, TPR domain immunophilins (IMM), such as FKBP52, Cyp40 or PP5 (protein phosphatase 5, an immunophilin homolog) can bind reversibly to the TPR acceptor site on receptor-bound Hsp90. TPR domains are indicated by black crescents. Details of Hsp90 heterocomplex assembly are reviewed in Pratt and Toft (1).

Figure 2. Regulation of polyQ AR degradation

Loss of cycling with Hsp90, such as following the addition of small molecule Hsp90 inhibitors or steroid-dependent conformational change of the polyQ AR, permits unfolding of the mutant protein (indicated by jagged steroid binding cleft). Substrate-bound Hsp70 then recruits chaperone dependent ubiquitin ligases such as CHIP to promote ubiquitination with subsequent degradation by the proteasome. (Modified from ref. 45.)