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Thanks, Maryse, for getting this on List. I passed on it. Ray Rayilyn Brown Board Member AZNPF Arizona Chapter National Parkinson's Foundation [log in to unmask] ----- Original Message ----- From: "M.Schild" <[log in to unmask]> To: <[log in to unmask]> Sent: Monday, June 25, 2007 2:09 AM Subject: New drug target for the treatment of Parkinson's disease > Researchers at the MassGeneral Institute for Neurodegenerative Disease > (MGH-MIND) have identified a potential new drug target for the treatment > of > Parkinson's disease and possibly for other degenerative neurological > disorders. > In an upcoming issue of the journal Science, the investigators describe > finding, in cellular and animal models, that blocking the action of an > enzyme > called SIRT2 can protect the neurons damaged in Parkinson's disease from > the > toxic effects of alpha-synuclein, a protein that accumulates in the brains > of > Parkinson's patients. The study, which also suggests that inhibiting this > pathway could help in the treatment of other conditions in which abnormal > proteins accumulate in the brain, is receiving early online release on the > Science Express website at http://www.sciencexpress.org. > "We have discovered a compelling new therapeutic approach for Parkinson's > disease, which we expect will allow our scientists , as well as those at > pharmaceutical and biotech companies , to pursue innovative new drugs that > will treat and perhaps even cure this disorder," says Aleksey Kazantsev, > PhD, > director of MGH-MIND Drug Discovery Laboratory, who led the Science > study. "Since the same sort of aggregation of misfolded proteins has been > reported in Huntington's and Alzheimer's diseases - as well as Lewy body > dementia, which also involves alpha-synuclein deposits - we plan to test > this > approach in those conditions as well." > Parkinson's disease , characterized by tremors, rigidity, difficulty > walking > and other symptoms , is caused by the destruction of brain cells that > produce > the neurotransmitter dopamine. In recent years researchers at several > centers > have been studying the role of alpha-synuclein accumulations in > dopamine-producing neurons, observed in patients with both inherited and > sporadic Parkinson's disease. MGH-MIND investigators have discovered that, > in > Parkinson's, the alpha-synuclein molecule folds abnormally and form > aggregates called inclusion bodies. Such inclusions of other abnormal > proteins are seen in several disorders, but whether inclusions are toxic > or > protective to neurons has been controversial. > In a paper published last year in the Proceedings of the National Academy > of > Sciences, a research team led by Kazantsev analyzed ways to reduce the > size > of inclusions containing misfolded versions of alpha-synuclein or of the > Huntington's disease-associated protein huntingtin. They found that a > compound called B2, which promotes the formation of larger inclusions, > paradoxically appeared to reduce toxicity in cellular disease models, > possibly by reducing the overall number of inclusions. > In the current study, the investigators began by seeking the mechanism > underlying the observed effects of B2. Assays of the compound's activity > against a panel of key enzymes identified only one significant association > , > a weak but selective inhibition of SIRT2, which is known to regulate the > cell > cycle and may have a role in aging. An experiment using RNA interference > to > suppress SIRT2 and a related enzyme in human cell lines expressing > alpha-synuclein confirmed that only the inhibition of SIRT2 reduced > alpha-synuclein toxicity. > Kazantsev's team then developed and identified more powerful inhibitors of > SIRT2, based on the structure of B2. One of these novel inhibitors called > AGK2 had 10 times the potency of B2 and was shown to protect > dopamine-producing neurons from alpha-synuclein toxicity in cultured rat > neurons and in an insect model of PD. Several additional compounds that > act > on the SIRT2 pathway have been identified, some which may be even better > than > AGK2 as candidates for drug development. > SIRT2 is known to act on a major protein component of microtubules, > cellular > structures that help move objects within cells, among other functions. The > researchers theorize that inhibiting SIRT2 might promote > microtubule-dependent transportation of alpha-synuclein into large > aggregates; or it could strengthen microtubules that have been > destabilized > by misfolded alpha-synuclein. > Kazantsev explains, "For Parkinson's disease, we can now pursue a > straightforward drug development process by identifying potent and > selective > candidates from this class of compounds that can be tested in animal > studies > and eventual human trials. One of the most satisfying aspects is how this > discovery validates our approach to drug discovery, which incorporates > both > the most advanced tools for screening candidate compounds and outstanding > collaboration with our clinical and scientific experts in human disease." > Kazantsev is an assistant professor of Neurology at Harvard Medical > School. > http://www.mgh.harvard.edu > > ---------------------------------------------------------------------- > To sign-off Parkinsn send a message to: > mailto:[log in to unmask] > In the body of the message put: signoff parkinsn ---------------------------------------------------------------------- To sign-off Parkinsn send a message to: mailto:[log in to unmask] In the body of the message put: signoff parkinsn