Dans les modeles animaux, le blocage de l´enzyme SIRT2 peut proteger les 
neurones contre les effetes toxiques de l´álpha synucleine qui s´accumule 
dans les cerveaux des PCP.
Ces memes aggregats se retrouvent dans la Mal. de Huntington et la MA.
Les chercheurs ont identifies quelques complexes qui pourraient agir contre l
´alphe synucleine dont le B2 et surtout le AGK2 qui lui, serait un modele 
pour un prjet de developpement de nouveau medicament
maryse



texte original:



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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