A major, multi-institutional study based at Harvard-affiliated Massachusetts General Hospital (MGH) has identified a promising treatment strategy for Huntington’s disease (HD).The team’s identification of a novel compound, MIND4, appears to protect against neurodegeneration in cellular and animal models of HD by means of two separate mechanisms — inhibiting a regulatory enzyme of the nervous system (SIRT2), and stimulating activity of the NRF2 pathway, which regulates the expression of protective, antioxidant proteins. The report will be published online in the journal Cell Chemical Biology.“Based on numerous studies, it has become evident that the pathologies of neurodegenerative diseases, including Huntington’s disease, are very complex, so targeting multiple pathways may help us achieve maximum therapeutic benefit,” said Aleksey Kazantsev, who led the study as an investigator at the MassGeneral Institute for Neurodegenerative Disease (MIND). “The lead compound identified in the current study has two distinct mechanisms, both of which are shown to be potentially neuroprotective and which we expect will have synergistic benefits.”Previous work from Kazantsev’s MIND team identified SIRT2 as a promising treatment target for Huntington’s as well as for Parkinson’s disease. Building on those findings, he and his collaborators from 12 research institutions in five countries began searching for a scaffold — a group of molecules with similar chemical structures — that could be the basis of more potent and selective SIRT2 inhibitors. Starting with the most powerful SIRT2-inhibiting compound they identified, which they called MIND4, they assembled a group of structurally similar compounds with varying levels of effectiveness.In investigating how MIND4 acted to inhibit SIRT2, the researchers were surprised to find that the top seven pathways activated by treatment with MIND4 were related to the oxidative stress response mediated by NRF2. Additional experiments indicated that activation of NRF2-mediated pathways did not depend on SIRT2 inhibition.“Finding that MIND4’s SIRT2 and NRF2 activities are independent of each other is a critical step for further drug development, which indicates that work to improve the potency of each activity should proceed separately,” said Kazantsev. “We still don’t know whether the neuroprotective results we observed in this study depend more on one activity or the other, but since MIND4, which produces both activities, was a better protectant than [a MIND4 derivative] which only activates NRF2, I speculate that both activities will be necessary.”He added, “MIND4 is a great starting template for drug development, and we have promising preliminary results in two mouse models. We also need to optimize the pharmacology to meet FDA requirements for a version we can test in human patients. Right now, we expect to have results regarding the mechanism behind NRF2 activation ready for submission soon.” Kazantsev recently joined the Cambridge, Mass.-based startup company Effective Therapeutics, LLC, but continues to collaborate with his colleagues at MGH and other institutions.Anne B. Young, former MGH chief of neurology and founder of MIND as well as Effective Therapeutics, said, “These multidisciplinary studies highlight new pathways that can be targeted for HD therapy but also very likely for other neurodegenerative diseases, too.”A pdf of the study is available here.
Press Association The 20-year-old’s transfer will be finalised once international clearance is received. Cardiff agreed a deal with FC Copenhagen last week and the player underwent his medical at the club’s Vale of Glamorgan training base on Monday. Cornelius will join up with his new team-mates next week after a short holiday. Denmark striker Andreas Cornelius has signed a five-year deal with Cardiff after passing his medical with the Premier League newcomers. “This is a dream come true for me,” Cornelius told Cardiff City Player. “I’ve been given a great opportunity and this is a very exciting project that’s taking place at Cardiff City. “I’m very happy to be here and to be playing for this club in the Premier League. “There were opportunities for me this summer and I had to think about what was the right thing to do, the correct step for me to take in terms of my career. “I was impressed by what the club is trying to do, the fact it has reached the Premier League and that it has a passionate fan base supporting it.” Cornelius added: “It’s been a busy few days as I graduated from university back home over the weekend. “Both school and football are very important to me, so I had to structure my plans in order to achieve in both. “I will link up with my new team-mates next Monday and look forward to preparing for the new season. “These are very exciting times and I’m looking forward to working with the manager and learning more about this squad.”
MATTHEW KUTZ/Herald photoCHAMPAIGN, Ill. — If you had read the local newspapers before the game, you probably would’ve believed that the Illinois Fighting Illini had almost no chance of beating the Wisconsin Badgers Saturday afternoon. Well, at least that’s how UW head coach Barry Alvarez felt.With a high-profile clash against co-Big Ten leader Penn State just on the horizon, it’s understandable that Alvarez was worried his team might overlook a downtrodden Illinois squad.”I was hoping they didn’t read the papers here too much, because it sure seemed like [the Illinois media] were down on their kids for this week’s game,” Alvarez said. “I didn’t want them to think it would be easy.”Well, any illusions the Badgers may have had of an easy game were put to rest Saturday, as the Illinois offense proved to be more than a handful for the Wisconsin defense. More succinctly, however, quarterback Tim Brasic was a handful for the Badgers.The junior wreaked havoc on the Wisconsin defensive front all day with his ability to get outside the pocket on scramble. And he made this effect known early. On Illinois’ second scoring drive, the Illini signal caller converted a pair of third downs, including one third-and-15 situation, with his legs, bringing his team within three points of UW.By the end of the first half, the Riverside, Ill., native had run roughshod over the Badgers’ defense for 48 yards, and by the end of the game, he’d increased that total to 116.”He just kept finding space to run,” sophomore linebacker Andy Crooks said. “He did a great job on the ground and I don’t know what we could’ve done differently. We were spying him and he kept getting yards.”Brasic’s ability to run against Wisconsin brought to the forefront the effect the absence of starting mike linebacker Mark Zalewski had on the defense. Sitting out after suffering a knee injury against Purdue, Zalewski is a player defensive coordinator Bret Bielema admitted would have drawn the task of stopping Brasic on Illinois’ option looks as well as on scrambles out of the pocket.”He was improved, but wasn’t improved enough to play,” Alvarez said of Zalewski’s status. “I am hoping [he’ll be able to play against Penn State], I think there’s a good chance. You can speculate he may not play but I have a feeling he’ll be ready to practice this week.”But without Zalewski at his disposal, Bielema tried a litany of different looks to stop the Illinois signal caller, at some points even taking out senior linebackers LaMarr Watkins and Dontez Sanders and replacing them with true freshmen DeAndre Levy and Jonathan Casillas.”I wasn’t happy with them at particular times but they get better each week and I think it’s important to them,” Bielema said of Levy and Casillas. “I want everyone to understand that, especially defensively with linebackers, the guys who are going to play are the guys who’re going to help us win.”But Brasic wasn’t just causing problems for the UW defensive linemen and linebackers. He did his fair share of damage through the air, amassing 277 yards and two touchdowns for Illinois, numbers the defense admits are unacceptable.”Once again this week we’re kind of the redheaded step-child, it’s something that’s not acceptable and something we’re definitely going to have to get straightened out before next week,” defensive lineman Mike Newkirk said.But Bielema isn’t ready to push the panic button just yet. The UW defensive coordinator knows things have gotten ugly at times for the defense, but with another scrambling quarterback on the horizon — one that has a more potent offense at his disposal — in Penn State’s Michael Robinson, he believes the corrections made in the next few days could be the difference in next week’s contest.”It hasn’t been pretty in any way this year but I think we knew that coming in,” Bielema said. “But they scrap, they claw and at the end I just asked for everybody’s eyes and said ‘You are a resilient group, you battle every week, no one can ever say you quit in a particular situation,’ which means they have a great amount of pride. This week they’ve just got to be able to do something special.”