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Study identifies novel Parkinson's
disease drug target
Blocking enzyme activity may also
reduce brain cell death in Huntington's, other disorders
BOSTON - June 21, 2007 - 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.
"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.
Co-authors of the Science report are first author Tiago
Outeiro, PhD, and co-authors Steve Altman, Allison Amore, Michele
Maxwell, PhD, Pamela McLean, PhD, Anne Young, MD, PhD, and Bradley
Hyman, MD, PhD, of MGH-MIND; Eirene Kontopoulos and Mel Feany, MD,
PhD, Brigham and Women's Hospital; Irina Kufareva, PhD, and Ruben
Abagyan, PhD, Scripps Research Institute; and Katherine Strathearn,
Catherine Volk, and Jean-Christophe Rochet, PhD, Purdue University.
The study was supported by private donations to MGH-MIND and grants
from the National Institutes of Health and the Massachusetts Biomedical
Research Corporation.
Massachusetts General Hospital, established in 1811, is the original
and largest teaching hospital of Harvard Medical School. The MGH
conducts the largest hospital-based research program in the United
States, with an annual research budget of more than $500 million
and major research centers in AIDS, cardiovascular research, cancer,
computational and integrative biology, cutaneous biology, human
genetics, medical imaging, neurodegenerative disorders, regenerative
medicine, systems biology, transplantation biology and photomedicine.
MGH and Brigham and Women's Hospital are founding members of Partners
HealthCare HealthCare System, a Boston-based integrated health care
delivery system.
Media Contact: Sue
McGreevey, MGH Public Affairs
Physician Referral Service: 1-800-388-4644
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