The cellular defense mechanism known as the heat shock response cranks up the production of stress proteins. The stress proteins, also called heat shock proteins, target misfolded proteins, many of which are then nudged toward degradation. This stress response may itself become overstressed, however, if protein misfolding is chronic. And the overstressed stress response may end up doing more harm than good.

This surprising result first emerged in an investigation of cystic fibrosis, a condition in which gene mutations result in misfolded versions of CFTR, an ion-channel protein. Ordinarily, the misfolded CFTR proteins are trapped by the heat shock response, which ensures that few of them ever reach the cell membrane and function as ion channels. The problem is, the misfolding of the CRTR proteins is chronic, and the heat shock response is always elevated.

The “always on” heat shock response is maladaptive, report scientists based at The Scripps Research Institute (TSRI). According to these researchers, who were led by senior investigator Professor William E. Balch, Ph.D., maladaptation alters protein structure-function relationships, impacts protein folding in the cytosol, and further exacerbates the disease state. What’s more, a maladaptive stress response is a problem not only in cystic fibrosis, but also in other conditions characterized by chronic protein misfolding. In particular, the researchers extended their findings from cystic fibrosis to alpha-1-antitrypsin deficiency (AATD), Niemann-Pick type C1 disease (NPC1), and Alzheimer’s disease (AD).

The researchers presented their results November 18 in the journal PLoS Biology, in an article entitled, “Modulation of the Maladaptive Stress Response to Manage Diseases of Protein Folding.” In this article, the researchers induced maladaptive stress responses, and attempted to moderate them, in several experimental models including patient-derived cell lines and primary epithelium, mouse brain tissue, and Caenorhabditis elegans.

“We show that down-regulation of this maladaptive stress response (MSR), through silencing of HSF1, the master regulator of the HSR, restores cellular protein folding and improves the disease phenotype,” wrote the authors. “We propose that restoration of a more physiological proteostatic environment will strongly impact the management and progression of loss-of-function and gain-of-toxic-function phenotypes common in human disease.”

“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, Ph.D., 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.”

TSRI collaborators at the University Medical Centre, Utrecht, the Netherlands, used a cystic fibrosis model consisting of clumps of tissue—“organoids”—derived from cystic fibrosis patients. In these organoids, the scientists inhibited HSF1 with a compound called triptolide and at the same time applied VX-809, a promising cystic fibrosis drug candidate. The two drugs together showed a powerful synergistic effect, producing a greater reduction in disease signs, compared to VX-809 treatment on its own.

The team also found a hint that a chronically overactive heat shock response may end up causing a general disruption of the general folding function in cells. In cells containing mutant CFTR, but not in those with normal CFTR, a luminescent enzyme that marks the capacity of cells to enforce proper protein folding indicated a major reduction in global folding capacity.

“This broad impairment presumably reduces the ability of cells to function correctly in many folding reactions, which would compound the disease pathology,” said Dr. Balch.

Dr. Balch and his TSRI colleagues confirmed that MSR also occurs in protein-misfolding conditions besides cystic fibrosis by using cell models of the genetic disorders alpha-1-antitrypsin deficiency and Niemann-Pick disease. In addition, TSRI collaborators at Northwestern University investigated a commonly used animal model of protein misfolding, in which a roundworm (C. elegans) overproduces the Alzheimer’s-associated amyloid beta 42 peptide in muscle cells. The worms’ muscle cells form aggregates of the peptide, and most of the affected worms develop paralysis. Again, HSF1 turned out to be overactive in these aggregate-filled muscle cells, and inhibiting HSF1 activity reduced the proportion of worms with paralysis, suggesting a strong evolutionary conservation of the maladaptive response.

To further establish the relevance to Alzheimer’s, another collaborator, this one at the University of California, San Diego, looked at standard gene-mutant mouse models of the disease and found a similar HSF1 overactivation in brain tissue, compared to none in ordinary, wild-type mice.

“In general, it appears that the chronic production of misfolded proteins can lead to this ‘maladaptive stress response,’ as we call it,” said Dr. Balch. “Reducing the maladaptive stress response as a first line of defense could have an important impact on the progression and pathology in many diseases—from cancer to viral infections.”