An enzyme known to be critical for the repair of damaged cells and the maintenance of cellular energy may be a useful target for new strategies to treat Huntington's disease (HD) and other disorders characterized by low cellular energy levels. In the August issue of Chemistry & Biology, a research team from the MassGeneral Institute for Neurodegenerative Disease (MIND) describes their discovery of a novel inhibitor of Poly (ADP-ribose) polymerase (PARP1) and their findings that PARP1 inhibitors can protect HD-affected cells from damage in laboratory assays.
"While PARP1 is essential for the repair of damaged DNA, we also know that, if overactivated, it can cause cell death by excessive energy depletion," says Aleksey Kazantsev, PhD, director of the MIND High Throughput Drug Screening Laboratory, who led the current study. "It has recently been shown that neurons from patients with Huntington's appear to be energy-deficient, so we hypothesized that modest stresses that would be tolerated by healthy cells could send HD cells below a viable energy threshold and that blocking PARP1 activation could be protective."
To test this hypothesis the MIND researchers first ran a computer search of their small-molecule library for potential novel inhibitors of PARP1, searching for those with structural similarities to known inhibitors. "Safety and efficacy of human drugs depends on many factors, so it's hard to predict which inhibitor would be most effective against a specific disorder. The more diverse novel inhibitors can be identified, the more chances there are of developing safe and effective drugs," Kazantsev explains.
Two candidate molecules were identified as potential PARP1 inhibitors based on their structure, and both of them were confirmed to inhibit the enzyme's activity in an in vitro assay. However, when tested using cultured human and rat cells, only one of the candidate molecules, K245-14, successfully prevented the death of cells in which PARP1 had been overactivated.
The next assays examined whether blocking PARP1 activity with K245-14 could reduce energy depletion in cells with the HD genetic mutation. Using cells from human HD patients and from a mouse model of the disorder, the MIND researchers compared the reactions of HD cells to oxidative stress caused by the application of hydrogen peroxide with the reactions of normal cells. Although all of the cells reacted with a loss of ATP, a key source of cellular energy, the HD cells – which had much lower ATP levels to begin with – were much more vulnerable to stress-induced energy loss. Inhibiting PARP1 by means of K245-14 reduced ATP loss in all tested cells and significantly protected against both energy loss and cell death in the HD cells.
"While we were pleased to observe these predicted protective effects in our experiments, validation of PARP1 as a useful HD drug target will require the testing of inhibitors in animal trials," Kazantsev explains. "The process of identifying the best candidates for trials will be very complex, since any drug treating a central nervous system disorder needs to penetrate the blood-brain barrier. We will be working with our collaborators at the Scripps Research Institute – world leaders in computational chemistry – to conduct a more comprehensive virtual screen and select additional promising candidates for drug development.
"Inhibition of PARP1 activity is thought to be potentially beneficial for treatment of cancer, neurodegenerative conditions such as Parkinson's disease, and over twenty other human disorders," he adds. "We envision broad therapeutic applications for small molecule inhibitors of PARP1." Kazantsev is an assistant professor of Neurology at Harvard Medical School.
Sue McGreevey | EurekAlert!
The importance of biodiversity in forests could increase due to climate change
17.11.2017 | Deutsches Zentrum für integrative Biodiversitätsforschung (iDiv) Halle-Jena-Leipzig
Win-win strategies for climate and food security
02.10.2017 | International Institute for Applied Systems Analysis (IIASA)
The WHO reports an estimated 429,000 malaria deaths each year. The disease mostly affects tropical and subtropical regions and in particular the African continent. The Fraunhofer Institute for Silicate Research ISC teamed up with the Fraunhofer Institute for Molecular Biology and Applied Ecology IME and the Institute of Tropical Medicine at the University of Tübingen for a new test method to detect malaria parasites in blood. The idea of the research project “NanoFRET” is to develop a highly sensitive and reliable rapid diagnostic test so that patient treatment can begin as early as possible.
Malaria is caused by parasites transmitted by mosquito bite. The most dangerous form of malaria is malaria tropica. Left untreated, it is fatal in most cases....
The formation of stars in distant galaxies is still largely unexplored. For the first time, astron-omers at the University of Geneva have now been able to closely observe a star system six billion light-years away. In doing so, they are confirming earlier simulations made by the University of Zurich. One special effect is made possible by the multiple reflections of images that run through the cosmos like a snake.
Today, astronomers have a pretty accurate idea of how stars were formed in the recent cosmic past. But do these laws also apply to older galaxies? For around a...
Just because someone is smart and well-motivated doesn't mean he or she can learn the visual skills needed to excel at tasks like matching fingerprints, interpreting medical X-rays, keeping track of aircraft on radar displays or forensic face matching.
That is the implication of a new study which shows for the first time that there is a broad range of differences in people's visual ability and that these...
Computer Tomography (CT) is a standard procedure in hospitals, but so far, the technology has not been suitable for imaging extremely small objects. In PNAS, a team from the Technical University of Munich (TUM) describes a Nano-CT device that creates three-dimensional x-ray images at resolutions up to 100 nanometers. The first test application: Together with colleagues from the University of Kassel and Helmholtz-Zentrum Geesthacht the researchers analyzed the locomotory system of a velvet worm.
During a CT analysis, the object under investigation is x-rayed and a detector measures the respective amount of radiation absorbed from various angles....
The quantum world is fragile; error correction codes are needed to protect the information stored in a quantum object from the deteriorating effects of noise. Quantum physicists in Innsbruck have developed a protocol to pass quantum information between differently encoded building blocks of a future quantum computer, such as processors and memories. Scientists may use this protocol in the future to build a data bus for quantum computers. The researchers have published their work in the journal Nature Communications.
Future quantum computers will be able to solve problems where conventional computers fail today. We are still far away from any large-scale implementation,...
15.11.2017 | Event News
15.11.2017 | Event News
30.10.2017 | Event News
21.11.2017 | Physics and Astronomy
21.11.2017 | Physics and Astronomy
21.11.2017 | Life Sciences