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UK researchers have found that several existing drugs which are already approved for other purposes induce autophagy, an alternate way to clear away the HD protein.
Editor's Comment:
Inducing autophagy as an alternate way to enhance the clearance of the HD protein is a very promising strategy for preventing or delaying the onset of Huntington's Disease. A new study by Professor David C. Rubinsztein and colleagues suggests new drugs that induce autophagy for the research pipeline. Understanding how these drugs work has also provided some new insights about Huntington's Disease.
Protein clearance, the UPS, and HD
After a protein is made, it needs to be folded correctly to be able to do its work in the cell. This doesn't always happen and misfolded proteins are targeted for degradation. The normal huntingtin's protein is degraded though the ubiquitin proteosome system (UPS). In the ubiquitin proteosome system, proteins which are not needed or which have misfolded are tagged for degradation by a small protein called ubiquitin. The unwanted protein is then moved into the proteosome, a barrel like protein complex, which breaks it down into amino acids which can then be recycled.
One theory holds that the UPS is impaired in Huntington's Disease. If that is true, it could explain quite a bit about HD pathology because the UPS appears to play an important role in many regulatory processes in the cell.
This theory is controversial, however. Some labs using certain methods have found evidence to suggest that it is and others using different methods have not. It is also possible that the conflicting findings can be explained because the researchers were looking at different points in the disease process (see http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=18047739 for a good review of the issues).
The UPS is an important line of investigation because of the potential for treatment and researchers are already looking into ways to target the UPS in case the theory proves to be true.
Inducing autophagy as a treatment strategy
Whether or not the UPS itself is impaired in Huntington's Disease, there is good evidence to suggest that it is not capable of handling the HD protein and that its clearance is mediated by an alternate method called autophagy.
Autophagy literally translates as 'self eating.' In this very old cellular house cleaning process (it's found in organisms from yeast to mammals), damaged parts of the cell, pathogens, and large proteins are surrounded and consumed.
Autophagy is even induced during times of starvation -- less essential parts of the cell will be consumed for nutrition. This may explain why caloric restriction initially helps the HD mice, because it induces autophagy.
A potential treatment strategy would be to safely induce autophagy to enhance the clearance of the HD protein. The one known way to induce autophagy with a medication has been through rapamycin, an old antibiotic. Studies reported here on the Lighthouse have shown that rapamycin is helpful in a variety of animal models of Huntington's Disease.
Researchers have been reluctant to bring rapamycin to clinical trials because the drug would need to be taken over many years and it has side effects at the levels needed for it to be effective, one of which is suppressing the immune system. The search has been on for alternatives and in an exciting new study, Professor David Rubinsztein and colleagues report that several drugs that are already FDA approved for other purposes also stimulate autophagy.
They screened 256 existing drugs in use for other medical conditions and found several which induce autophagy. Two drugs are of particular interest, verapamil and clonidine. Verapamil is prescribed for high blood pressure and many people take it for years. It is an L-type calcium channel antagonist and stimulates autophagy by reducing the influx of calcium into cells. Calcium handling is known to be a problem in HD.
Clonidine is prescribed for migraines. It is a regular of inositol trisphosphate (IP3) levels. It induces autophagy through the reduction of cAMP. cAMP, which stands for cyclic adenosine monophosphate, is a molecule which is responsible for a number of functions in the cell, including regulating the passage of calcium through ion channels. cAMP is known to be elevated in HD.
Although these drugs work differently, they both affect different parts of the same cyclical pathway in which cAMP regulates IP3 levels which increase calpain activity, which cleaves and then activates Gs alpha, which in turn regulates cAMP levels. Intervention at any point was shown to be effective in inducing autophagy in the study. Interestingly, this pathway is independent of the one in which rapamycin induces autophagy.
The results for verapamil and clonidine look good in fruitflies and zebrafish and the drugs will be tried next in a mouse model.
One treatment possibility they suggest is a combination of one of the drugs identified in the study and rapamycin since they work by different pathways. The idea is that a lower dose would be needed for each, reducing side effects.
Some new insights
In addition to the identification of drugs to be tested as potential treatments, the study is also important because it may answer some questions about Huntington's Disease.
If autophagy is a normal cellular process for the clearance of large proteins and is capable of handling the HD protein, why isn't it doing its job? The answer appears to be the increased levels of calpain, a calcium dependent protease which plays various functions in the cell. Calpain is increased in Huntington's Disease and inhibits autophagy. Inhibiting calpain increases autophagy.
Further, this study suggests a link between excitotoxicty and reduced autophagy. The excitotoxicity theory in HD is an old one. The idea is that neurons are unusually sensitive to glutamate in HD, overstimulating the glutamate receptors which in turn leads to an influx of calcium into the cell. The study shows that an influx of calcium inhibits autophagy and a reduction induces it.
I found something else to be interesting. Although this is not covered in the study, I am wondering about the role of cAMP in HD symptoms. Research reported last year by Yale researchers found that there are ion channels on the dendritic spines of neurons in the prefrontal cortex which open in response to cAMP. When that happens, information can't get to the cell and the strength of higher brain networks is reduced. Normally cAMP is regulated by nearby alpha-2A adrenergic receptors but this process can be dysregulated in ADHD and in schizophrenia. Since cAMP is elevated in HD, could this be the cause of the impairment of executive dysfunction in Huntington's Disease as well?
"Our data reveal how the brain's arousal systems influence the cognitive networks that subserve working memory-which plays a key role in abstract thinking, planning, and organizing, as well as suppressing attention to distracting stimuli," said Amy Arnsten, lead author and neurobiology professor at Yale in a press release written at the time.
The Rubinsztein autophagy research is exciting and the Lighthouse will keep following it.
References
Janet E Davies, Sovan Sarkar, and David C Rubinsztein. "The ubiquitin proteasome system in Huntington's disease and the spinocerebellar ataxias." BMC Biochemistry 2007 Nov 22;8 Suppl 1:S2.
Min Wang, Brian Ramos, Constantinos Paspalas, Yousheng Shu, Arthur Simen, Alvaro Duqye, Avis Brennan, Susheel Vijayraghavan, Anne Dudley, Eric Nou, David McCormick, James Mazer, and Amy Arnsten. "Alpha2A-adrenoceptors strengthen working memory networks by inhibiting cAMP-HCN channel signaling in prefrontal cortex."Cell 129: 1-14 (April 20, 2007)
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the press release
Research funded by the Wellcome Trust has provided a number of promising new drug targets for Huntington's disease, a neurodegenerative disease. Scientists at the University of Cambridge have identified a number of candidate drugs to investigate further which encourage cells to "eat" the malformed proteins that lead to the disease.
Huntington's disease is one of a number of degenerative diseases marked by build up of a malformed proteins in brain cells, mainly in the basal ganglia and the cerebral cortex. Normally, cells dispose of or recycle their waste material, including unwanted or misfolded proteins, through a process known as autophagy, or 'self-eating'.
The group of Professor David Rubinsztein, a Wellcome Trust Senior Clinical Fellow at the University of Cambridge, has previously shown that stimulating autophagy in the cells can be an effective way of preventing the malformed proteins from building up. However, there are currently no treatments available that slow the neurodegeneration in people with Huntington's disease. Rapamycin, an immunosuppressant used to lower the body's natural immunity in patients who receive kidney transplants, is the most promising candidate drug currently available but can have significant side effects.
Now, in research published today online in the journal Nature Chemical Biology, Professor Rubinsztein and colleagues have shown that a number of FDA-approved drugs for treatments such as migraine and hypertension are able to stimulate autophagy in fruit flies and zebrafish through unexpected pathways.
"By screening a number of drugs that have already been shown to be safe in humans, we have been able to identify some unexpected and very promising pathways involved in Huntington's," says Professor Rubinsztein. "In collaboration with Cahir O’Kane’s group in Cambridge and Summit Plc, we have shown that these drugs can alleviate the toxicity of the Huntington’s disease mutation in cell-based, fly and zebrafish models. The big question for us is whether they will do the same in humans."
One of the drugs tested, verapamil, which is currently used to treat high blood pressure and heart arrhythmias (among other indications), inhibits the influx of calcium into cells which, in turn, appears to regulate autophagy. Similarly, clonidine, currently used to treat hypertension or migraine, appears to work on autophagy by decreasing levels of cAMP, a molecule that is important in many biological processes.
If the drugs can stimulate autophagy effectively over long-term periods in human brains, then they may have the potential to help delay the onset of Huntington's disease. The candidate drugs are relatively safe and well tolerated when used to treat the diseases they were designed for. A minimal side-effect profile would be highly desirable for a drug treatment aiming to delay the onset or slow the progress of Huntington's. Such drugs may need to be taken for decades, and even moderate side effects may discourage people from taking them over a long period.
"We know the genetics of Huntington's disease and can predict the majority of people at risk," says Professor Rubinsztein. "If we can find a safe, well tolerated drug, then a person at risk could be placed on a drug regime to help prevent onset. It is much easier to stop something happening than having to treat it once it has started."
Professor Rubinsztein and colleagues will shortly begin testing the drugs in other animal models to evaluate their safety and efficacy.
the journal abstract
Autophagy is a major clearance route for intracellular aggregate-prone proteins causing diseases such as Huntington's disease. Autophagy induction with the mTOR inhibitor rapamycin accelerates clearance of these toxic substrates. As rapamycin has nontrivial side effects, we screened FDA-approved drugs to identify new autophagy-inducing pathways. We found that L-type Ca2+ channel antagonists, the K+ATP channel opener minoxidil, and the Gi signaling activator clonidine induce autophagy. These drugs revealed a cyclical mTOR-independent pathway regulating autophagy, in which cAMP regulates IP3 levels, influencing calpain activity, which completes the cycle by cleaving and activating Gsalpha, which regulates cAMP levels. This pathway has numerous potential points where autophagy can be induced, and we provide proof of principle for therapeutic relevance in Huntington's disease using mammalian cell, fly and zebrafish models. Our data also suggest that insults that elevate intracytosolic Ca2+ (like excitotoxicity) inhibit autophagy, thus retarding clearance of aggregate-prone proteins.
Source: Nature Chemical Biology published online 23 March 2008
Printed: 11 Sep 2010
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Article posted to www.HDlighthouse.org on: 03-28-2008
For more on this topic search on: autophagy, calcium, calpain, ubiquitin proteosome system, verapamil, clonidine