The NAD-dependent deacetylase Sir2 was initially identified as a mediator of replicative lifespan in budding yeast and was subsequently shown to modulate longevity in worms and flies1, 2. Its mammalian homologue, SIRT1, seems to have evolved complex systemic roles in cardiac function, DNA repair and genomic stability. Recent studies suggest a functional relevance of SIRT1 in normal brain physiology and neurological disorders. However, it is unknown if SIRT1 has a role in higher-order brain functions. We report that SIRT1 modulates synaptic plasticity and memory formation via a microRNA-mediated mechanism. Activation of SIRT1 enhances, whereas its loss-of-function impairs, synaptic plasticity. Surprisingly, these effects were mediated via post-transcriptional regulation of cAMP response binding protein (CREB) expression by a brain-specific microRNA, miR-134. SIRT1 normally functions to limit expression of miR-134 via a repressor complex containing the transcription factor YY1, and unchecked miR-134 expression following SIRT1 deficiency results in the downregulated expression of CREB and brain-derived neurotrophic factor (BDNF), thereby impairing synaptic plasticity. These findings demonstrate a new role for SIRT1 in cognition and a previously unknown microRNA-based mechanism by which SIRT1 regulates these processes. Furthermore, these results describe a separate branch of SIRT1 signalling, in which SIRT1 has a direct role in regulating normal brain function in a manner that is disparate from its cell survival functions, demonstrating its value as a potential therapeutic target for the treatment of central nervous system disorders.From press release:The same molecular mechanism that increases life span through calorie restriction may help boost memory and brainpower, researchers at MIT's Picower Institute for Learning and Memory report in the July 11 issue of Nature.Resveratrol, found in wine, has been touted as a life-span enhancer because it activates a group of enzymes known as sirtuins, which have gained fame in recent years for their ability to slow the aging process. Now MIT researchers report that Sirtuin1 -- a protein that in humans is encoded by the SIRT1 gene -- also promotes memory and brain flexibility.The work may lead to new drugs for Alzheimer's disease and other debilitating neurological diseases."We demonstrated previously that Sirtuin1 promotes neuronal survival in age-dependent neurodegenerative disorders. In our cell and mouse models for Alzheimer's disease, SIRT1 promoted neuronal survival, reduced neurodegeneration and prevented learning impairment," said Li-Huei Tsai, director of the Picower Institute and lead author of the study."We have now found that SIRT1 activity also promotes plasticity and memory," said Tsai, Picower Professor of Neuroscience and a Howard Hughes Medical Institute investigator. "This result demonstrates a multi-faceted role of SIRT1 in the brain, further highlighting 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."In separate work at MIT, researchers discovered that the sir2 (silent information regulator) gene is a key regulator of longevity in both yeast and worms. Ongoing studies are exploring whether this highly conserved gene also governs longevity in mammals.The mammalian version of the gene, SIRT1, seems to have evolved complex systemic roles in cardiac function, DNA repair and genomic stability. SIRT1 is thought to be a key regulator of an evolutionarily conserved pathway that allows organisms to cope with adversity. These genes and the enzymes they produce are part of a feedback system that enhances cell survival during times of stress, especially a lack of food.Recent studies 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 shows that SIRT1 enhances synaptic plasticity, the connections among neurons, and memory formation. These findings demonstrate a new role for SIRT1 in cognition and a previously unknown mechanism by which SIRT1 regulates these processes.MicroRNAs are small RNA molecules encoded in the genomes of plants and animals. These gene regulators are involved in many aspects of normal and abnormal brain function. The Picower study found that SIRT1 aids memory and synaptic plasticity through a previously unknown microRNA-based mechanism: SIRT1 keeps a specific microRNA in check, allowing key plasticity proteins to be expressed.In addition to helping neurons survive, SIRT1 also has a direct role in regulating normal brain function, demonstrating its value as a potential therapeutic target for the treatment of the central nervous system.
1.Jun Gao Wen-Yuan Wang, Ying-Wei Mao, Johannes Gräff, Ji-Song Guan, Ling Pan, Gloria Mak, Dohoon Kim, Susan C. Su and Li-Huei Tsai A novel pathway regulates memory and plasticity via SIRT1 and miR-134 Nature 2010 July MIT's Picower Institute for Learning and Memory