Re: New drug target for the treatment of Parkinson's disease

[rayilynlee <rayilynlee@xxxxxxx>]

Thanks, Maryse, for getting this on List.  I passed on it. Ray
Rayilyn Brown
Board Member AZNPF
Arizona Chapter National Parkinson's Foundation
rbrown@xxxxxxxxx
----- Original Message -----
From: "M.Schild" <mmoo@xxxxxxxxxxxxxxxx>
To: <PARKINSN@xxxxxxxxxxxxxxxxxxxx>
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
>
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