Heat shock proteins such as HSP70 are molecular chaperones involved in cellular housekeeping processes that clear out damaged or misfolded proteins. Their activity increases in response to heat, toxins, and various other forms of cellular stress, and dialing up the activity of heat shock proteins is involved in a number of methods demonstrated to slow aging in laboratory animals. There are a few programs underway in the research community aimed at producing therapies that increase heat shock protein activity, especially for neurodegenerative conditions involving protein aggregates, but nothing that has yet made the leap into later stages of development and higher levels of funding:
Reducing the levels of toxic protein aggregates has become a focus of therapy for disorders like Alzheimer's and Parkinson's diseases, as well as for the general deterioration of cells and tissues during aging. One approach has been an attempt to influence the production or activity of a class of reparative chaperones called heat shock proteins (HSPs), of which HSP70 is a promising candidate. Manipulation of HSP70 expression results in disposal of misfolded protein aggregates that accumulate in aging and disease models. Recently, HSP70 has been shown to bind specifically to an amino-terminal sequence of a human diffusible survival evasion peptide (DSEP), dermcidin. This sequence includes CHEC-9, an orally available anti-inflammatory and cell survival peptide.
In the present study, we found that the CHEC-9 peptide also binds HSP70 in the cytosol of the cerebral cortex after oral delivery in normal rats. Western analysis suggested that peptide treatment increased the level of active HSP70 monomers from the pool of chaperone oligomers, a process that may be stimulated by potentiation of the chaperone's adenosine triphosphatase (ATPase). In these samples, a small but consistent gel shift was observed for glyceraldehyde 3-phosphate dehydrogenase (GAPDH), a multifunctional protein whose aggregation is influenced by HSP70. CHEC-9 treatment of an in vitro model of α-synuclein aggregation also results in HSP70-dependent dissolution of these aggregates.
HSP70 oligomer-monomer equilibrium and its potential to control protein aggregate disease warrant increased experimental attention, especially if a peptide fragment of an endogenous human protein can influence the process.