Heat Shock Proteins as a Basis for Tackling Protein Aggregation in Neurodegenerative Diseases

Neurodegenerative conditions are largely characterized by the aggregation of a few altered proteins that are prone to forming solid deposits in and around neurons. Tissues, such as the brain, made up of long-lived cells, such as neurons, are particularly vulnerable to this sort of dysfunction, as they cannot dilute harmful protein aggregates by cell division, and dysfunctional cells are not readily destroyed and replaced. Cells must rely upon internal quality control mechanisms such as the presence of chaperone proteins responsible for chasing down misfolded or otherwise problematic proteins, and ensuring they are refolded correctly or recycled via autophagy.

The quality control mechanisms of chaperone mediated autophagy are known to be important in aging. Increased autophagic activity is associated with many of the means of modestly slowing aging demonstrated in laboratory animals in past decades. Autophagy declines with age, and this is thought to be important in the development of neurodegenerative conditions precisely because neurons are heavily reliant on quality control to maintain function. Researchers are interested in finding ways to build therapies for age-related conditions based on upregulation of autophagic activity, and, as noted in today's open access paper, the class of chaperone proteins called heat shock proteins are one prominent area of investigation.

Small Heat Shock Proteins, Big Impact on Protein Aggregation in Neurodegenerative Disease

Maintenance of cellular protein homeostasis (proteostasis) is crucial for cell function and survival. Neurons are particularly sensitive to dysregulated proteostasis as evidenced by the accumulation and aggregation of amyloidogenic proteins, which are a hallmark of neurodegenerative disease. Cellular molecular chaperone systems modulate proteostasis, and, therefore, are primed to influence aberrant protein-induced neurotoxicity and disease progression. Molecular chaperones have a wide range of functions from facilitating proper nascent folding and refolding to degradation or sequestration of misfolded substrates.

ATP-dependent chaperones, like the 70 kDa heat shock protein (Hsp70) and the 90 kDa heat shock protein (Hsp90), facilitate refolding, degradation, or sequestration of these misfolded proteins. Small heat shock proteins (sHsps) that lack an ATPase domain and are between 12 and 43 kDa are a class of molecular chaperones that typically associate early with misfolded proteins. These interactions hold proteins in a reversible state that helps facilitate refolding or degradation by other chaperones and co-factors.

Potential therapeutic strategies that aim to modulate endogenous sHsp expression or phosphorylation generally suffer from a lack of specificity for the sHsp family, let alone for discrete sHsps. Heat stress-responsive sHsps can be activated by drugs that generate a challenge to proteostasis, which includes proteasome inhibitors (e.g. Bortezomib), Hsp90 inhibitors (e.g. 17-AAG), and oxidative stress inducers (e.g. terrecyclic acid). However, these treatments also induce expression of other molecular chaperone families (e.g. Hsp70 and Hsp40) and are not specific for sHsp activation. Efforts to identify Hsp co-inducers, substances that potentiate stress responses without inducing a primary stress response on their own, may offer improved selectivity.

Small molecules that interact with sHsps may be a promising strategy for therapeutics, but the nature of this family of chaperones makes drugability difficult. There are no known small molecule ligands to use as a scaffold to start from. The dynamic nature of these proteins taunt the idea of engineering a high affinity binding drug; indeed, these promiscuous proteins likely have many client binding sites with a variety of conformations.

The diversity of sHsps from different organisms, from bacteria to humans, provides a rich set of proteins to explore for aggregation prevention activity. For example, a sHsp from a parasite was shown to be a potent inhibitor of amyloid-β fibrillation and reduced associated toxicity in a neuroblastoma cell model. Specific mutant or engineered sHsp variants, with altered oligomeric structure or client interactions, may prove to have increased chaperone activity towards amyloidogenic proteins. Small peptides derived from human HspB4 and HspB5 sequences, termed mini-chaperones, display chaperone-like activity. One of these constructs reduced cellular toxicity of amyloid-β.