“Protein misfolding” diseases such as cystic fibrosis and Alzheimer’s may be seriously exacerbated by the body’s own response against that misfolding, according to a new study led by scientists at The Scripps Research Institute (TSRI).
The researchers examined patient cells and animal models of several diseases that feature chronic protein misfolding and found that in each case, a cellular defense system against protein misfolding, called the “heat shock response,” was overactive. Reducing its activity lessened the signs of disease and enhanced the effects of existing therapeutics.
“This has important implications for the treatment of many human diseases,” said TSRI Professor William E. Balch, PhD, who was senior investigator for the study.
The research, reported in PLoS Biology, focused initially on cystic fibrosis, a genetic disease that causes recurrent lung infections and cuts life expectancy in half.
Heat Shock Mystery
Nearly all cystic fibrosis patients have a particular mutation (a deletion of the amino acid phenylalanine at position 508, known as F508-del) in both copies of the gene that codes for CFTR, an ion-channel protein that normally helps regulate cellular chloride levels in the lungs and other tissues. Mutant CFTR protein is structurally unstable, tends to fold abnormally and thus usually ends up trapped by cellular “chaperone molecules” (folding helpers) in the interior of the cell, where it is degraded. Only a small percentage of the mutant CFTR protein reaches the cell membrane and functions as ion channels.
As Balch’s and other laboratories have shown in recent years, the chaperones that trap mutant CFTR are part of the heat shock response, a powerful system that evolved to defend cells against protein misfolding caused by excess heat, oxidation and other stress factors.
“The conventional view in the field of misfolding diseases for many years has been that boosting the heat shock response and chaperone levels to improve protein folding should be therapeutic in many protein-misfolding diseases,” said Daniela M. Roth, PhD, a research associate who led the study in the Balch laboratory. “That may not be the case when misfolded proteins are produced chronically, and the heat shock response stays elevated.”
In the new study, the team first confirmed that heat shocking bronchial epithelial cells – an important affected cell type in cystic fibrosis – leads to the near-total trapping and degradation of mutant CFTR. The scientists then reproduced the same increased-trapping effect at normal temperature by turning up the heat shock response artificially – via the overproduction of an active form of HSF1, a transcription factor protein that serves as the main “on switch” for the response.
Source: The Scripps Research Institute