The first study to modulate the heat shock response in the mouse model of Huntington disease (HD) has delivered two major findings: that it worked, as theorized, to improve some clinical and laboratory measures of disease progression, and that the improvements were only temporary as the mice aged.
Neurologists and others familiar with the paper disagreed on which was more important: that the agent worked at all, suggesting a potential route toward clinical application, or that it stopped working, suggesting that a more fundamental age-related phenomenon must be targeted.
The study of HSP990, the first to test an agent capable of crossing the blood-brain barrier to ramp up the heat shock response in the mouse brain, was published in the August edition of the Journal of Clinical Investigation.
A decade of prior research has shown that inhibiting heat shock protein 90 (HSP90) activates the heat shock response, the primary means by which cells hunker down to survive stressful environments. Heat and other stressors cause proteins to misfold; the heat shock response sends in a variety of so-called “chaperone” proteins to re-fold those other proteins back into their proper shapes, or to usher them out of the cell. In the case of Huntington disease (HD), the question that has perplexed researchers is why the misfolded mutant huntingtin protein should aggregate inside the brain, despite the presence of normal levels of HSP.
Previous studies in cell and fly models of HD had shown that inhibiting HSP90 to activate the heat shock response suppresses mutant huntingtin aggregation, but until now, the blood-brain barrier (BBB) in mammals had made it difficult to translate those findings into mammals.
“The development of a BBB permeable HSP90 inhibitor (HSP990) meant that we were able to test the efficacy of this approach in a mouse model of HD,” said the first study author John Labbadia, a doctoral candidate in medical and molecular genetics at King's College London School of Medicine, in an e-mail to Neurology Today.
His group used both the R6/2 transgenic and HdhQ150 knockin mouse models of HD. They found that HSP990 treatment activated the heat shock response, reduced aggregate load and improved some — but not all — of the physical signs of the disorder in the mice. It did not improve weight loss, forelimb grip strength or exploratory activity in the mice, but did improve the HD mice's performance on a measure of balance and motor coordination.
But as Labbadia stated in his e-mail: “Surprisingly, we found that the beneficial effects of HSP990 treatment were transient and coincided with a progressive impairment in the ability of HD mice to activate the heat shock response. Our findings suggest that changes in the composition and organization of the DNA/protein complexes (chromatin architecture) surrounding heat shock response genes underlies this phenomenon, and suggests that impairment of the heat shock response may be a fundamental aspect of HD.”
The co-author of a commentary accompanying the study agreed that the finding of a transient improvement should lead researchers in a fresh direction, beyond simply trying to increase HSP levels.
“The heat shock response itself is becoming impaired,” said James Shorter, PhD, assistant professor in the department of biochemistry and biophysics at the Perelman School of Medicine in the University of Pennsylvania. “That was a surprising response. There had been a lot of optimism about this approach of HSP levels. It's disappointing that it doesn't continue to work. But it tells us something about the nature of Huntington disease, and that we have to focus on this impairment of the heat shock response.”
Richard I. Morimoto, PhD, Bill and Gayle Cook Professor of Biology and director of the Rice Institute for Biomedical Research at Northwestern University's Center for Genetic Medicine, had a different view.
“What's surprising is that the treatment worked even a little,” Dr. Morimoto said. “There was no way this compound should have worked. HSP990 is being used for anti-cancer therapies, for multiple myeloma, and is designed to kill cancer cells because it destroys a whole set of critical proteins in the cell. Activation of the heat shock response is just a side effect of the drug. The fact that it worked even for a while in the HD mice tells you how promising the approach could be if one uses a new class of what I call chaperone therapeutics, targeted to enhance the chaperone system without killing all those other proteins that HSP990 does to attack cancer.”
Dr. Morimoto is a co-founder of Proteostasis Therapeutics of Cambridge, MA, which is developing small-molecule agents designed to enhance and maintain proper protein folding in a variety of age-related neurodegenerative disorders.
“I'm sure the investigators were disappointed they did not have a stronger and prolonged effect. But why would anyone expect that a drug developed to treat cancer can be repurposed and function as a therapeutic for Huntington disease? Because it worked for the period that it did, I see it as a great support for the idea that a drug properly targeted to HSP and the chaperones may be very efficacious and may have prolonged benefits.”
A neurologist who specializes in the study of neurodegenerative disorders said that both approaches — enhancing the heat shock response, and learning why it progressively fails as animals age — have merit.
“This paper does show a proof principle in good animal models of HD that enhancing the heat shock response through a compound like this actually can have a positive effect,” said Henry L. Paulson, MD, PhD, Lucile Groff Professor of Neurology at the University of Michigan and director of the Michigan Institute for Neurodegenerative Diseases. “That's very important.”
But, he added, “the second very important thing about this study is the transience of the benefit. What is it that happens in our brains as we age that make these diseases manifest as we get older? This article is getting to that. As we age, there are changes at the chromatin level that make the neurons less able to mount a response to proteomic injury. That could be contributing to the disease itself.”
The commentary co-authored by Dr. Shorter notes that because HSP90 controls many necessary cellular functions, suppressing it with an agent like HSP990 is probably not the best way to rescue the heat shock response. It cites a 2010 paper in PLoS Biology about a small molecule, Heat Shock Factor 1 (HSF1A). The agent, according to the commentary, “increased the expression levels of several chaperones and consequently diminished the toxicity of polyglutamine proteins in mammalian cell culture and Drosophila models. We suggest that brain-penetrant variants of HSF1A and other potential small molecules that activate HSF1 without inhibiting HSP90 should also be explored in mouse models of HD.”
THE LINK BETWEEN AGING AND HUNTINGTON DISEASE
Another approach to targeting the link between aging and Huntington disease was described in a paper published in the September issue of the Journal of Clinical Investigation. The study, led by Morris F. White, PhD, of Harvard Medical School and the Howard Hughes Medical Institute, showed that modulating levels of the signaling protein insulin receptor substrate 2 (IRS2) changes disease progression in a mouse model of HD. Genetic variants of the HD mice with reduced IRS2 levels had twice the lifespan of standard HD mice, while variants with increased IRS2 had half the normal HD lifespan.
While no drug has been shown to affect IRS2 levels, Dr. White told Neurology Today that HD patients might benefit by restricting calories and increasing exercise levels to reduce the amount of insulin in the brain.
Labbadia J, Cunliffe H, Weiss A, et al. Altered chromatin architecture underlies progressive impairment of the heat shock response in mouse models of Huntington disease. J Clin Invest
Shorter J, Jackrel ME. Shock and awe: unleashing the heat shock responose to treat Huntington disease. J Clin Invest
Neef DW, Turski ML, Thiele DJ. Modulation of heat shock transcription factor 1 as a therapeutic target for small molecule intervention in neurodegenerative disease. PLoS Biol
Sadaqurski M, Cheng Z, Rosso A, et al. IRS2 increases mitochondrial dysfunction and oxidative stress in a mouse model of Huntington disease. J Clin Invest
2011; E-pub Sept 19.