Sirtuin1, which previously has been linked to slowing aging, also promotes memory and brain flexibility, according to researchers at MIT's Picower Institute for Learning and Memory. Their findings appear in the July 11 issue of Nature in a paper titled “A novel pathway regulates memory and plasticity via SIRT1 and miR-134.”
Recent studies have linked SIRT1 to normal brain physiology and neurological disorders. However, it was unknown if SIRT1 played a role in higher-order brain functions.
The Picower Institute study demonstrates a new role for SIRT1 in cognition and a previously unknown mechanism by which SIRT1 regulates these processes. The team found that SIRT1 enhances synaptic plasticity and memory formation. They also found that SIRT1 aids memory and synaptic plasticity by keeping a specific miRNA in check, allowing key plasticity proteins to be expressed.
Activation of SIRT1 enhances, whereas its loss-of-function impairs, synaptic plasticity. These effects were mediated via post-transcriptional regulation of cAMP response binding protein (CREB) expression by a brain-specific miRNA, miR-134.
SIRT1 normally functions to limit expression of miR-134 via a repressor complex containing the transcription factor YY1. Unchecked miR-134 expression following SIRT1 deficiency results in the downregulated expression of CREB and brain-derived neurotrophic factor, thereby impairing synaptic plasticity.
These results describe a separate branch of SIRT1 signaling, in which SIRT1 has a direct role in regulating normal brain function in a manner that is disparate from its cell-survival functions. “We demonstrated previously that Sirtuin1 promotes neuronal survival in age-dependent neurodegenerative disorders,” says Li-Huei Tsai, director of the Picower Institute and lead author of the study.
“This result demonstrates a multifaceted role of SIRT1 in the brain and further highlights its potential as a target for the treatment of neurodegeneration and conditions with impaired cognition, with implications for a wider range of central nervous system disorders,” adds Tsai, who is also Picower professor of neuroscience and a Howard Hughes Medical Institute investigator.