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Crystallographic structure of yeast sir2 complexed with ADP and a histone H4 peptide. Credit: MIT
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Over the past 20 years, biologists have
shown that proteins called sirtuins can slow the aging process in many animal
species.
Now an MIT team led by Professor Li-Huei
Tsai has revealed that sirtuins can also boost memory and brainpower—a finding
that could lead to new drugs for Alzheimer’s disease and other neurological
disorders.
Sirtuins’ effects on brain function,
including learning and memory, represent a new and somewhat surprising role,
says Tsai, the Picower Professor of Neuroscience and an investigator of the
Howard Hughes Medical Institute. “When you review the literature, sirtuins are
always associated with longevity, metabolic pathways, calorie restriction,
genome stability, and so on. It has never been shown to play a role in synaptic
plasticity,” she says.
Synaptic plasticity—the ability of
neurons to strengthen or weaken their connections in response to new
information—is critical to learning and memory. Potential drugs that enhance
plasticity by boosting sirtuin activity could help patients with neurological
disorders such as Alzheimer’s, Parkinson’s and Huntington’s diseases, says
Tsai.
A protein with many roles
Sirtuins have received much attention in recent years for their
life-span-boosting potential, and for their link to resveratrol, a compound
found in red wine that has shown beneficial effects against cancer, heart
disease and inflammation in animal studies.
MIT Biology Professor Leonard Guarente
discovered about 15 years ago that the SIR2 gene regulates longevity in yeast.
Later work revealed similar effects in worms, mice and rats.
More recently, studies have shown that
one mammalian version of the gene, SIRT1, protects against oxidative stress
(the formation of highly reactive molecules that can damage cells) in the heart
and maintains genome stability in multiple cell types. SIRT1 is thought to be a
key regulator of an evolutionarily conserved pathway that enhances cell
survival during times of stress, especially a lack of food.
In 2007, Tsai and her colleagues showed
that sirtuins (the proteins produced by SIR or SIRT genes) protect neurons
against neurodegeneration caused by disorders such as Alzheimer’s. They also
found that sirtuins improved learning and memory, but believed that might be
simply a byproduct of the neuron protection.
However, Tsai’s new study, funded by
National Institutes of Health, the Simons Foundation, the Swiss National
Science Foundation and the Howard Hughes Medical Institute, shows that sirtuins
promote learning and memory through a novel pathway, unrelated to their ability
to shield neurons from damage. The team demonstrated that sirtuins enhance
synaptic plasticity by manipulating tiny snippets of genetic material known as
microRNA, which have recently been discovered to play an important role in
regulating gene expression.
Specifically, the team showed that
sirtuins block the activity of a microRNA called miR-134, which normally halts
production of CREB, a protein necessary for plasticity. When miR-134 is
inhibited, CREB is free to help the brain adjust its synaptic activity.
Mice with the SIRT1 gene missing in the
brain performed poorly on several memory and learning tests, including
object-recognition tasks and a water maze.
“Activation of sirtuins can directly
enhance cognitive function,” says Tsai. “This really suggests that SIRT1 is a
very good drug target, because it can achieve multiple beneficial effects.”
Raul Mostoslavsky, assistant professor
of medicine at Harvard
Medical School,
says the findings do suggest that activating SIRT1 could benefit patients with
neurodegenerative diseases. “However, we will need to be very cautious before
jumping to conclusions,” he says, “since SIRT1 has (multiple) effects in
multiple cells and tissues, and therefore targeting specifically this brain function
will be quite challenging.”
Tsai and her colleagues are now studying
the mechanism of SIRT1’s actions in more detail, and are also investigating
whether sirtuin genes other than SIRT1 influence memory and learning.
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