Finding a sirtuin truth in Huntington's disease

The sirtuins are a conserved family of primarily NAD-dependent deacetylase proteins and have garnered much attention since the first report that the yeast sirtuin Sir2 can extend lifespan in this organism1. After more than 15 years of study, a central role for sirtuins in nutrient sensing is well established, and there is strong evidence to suggest that sirtuins are an integrative link between metabolic control and transcriptional regulation, although the importance of sirtuins in promoting lifespan extension is debatable2. Sirtuins have been shown to be necessary for mediating the beneficial effects of caloric restriction, and caloric restriction in mouse models of neurodegeneration was found to ameliorate disease symptoms and pathology, leading to the controversial notion that sirtuins might represent important therapeutic targets for neurodegenerative disorders. In this issue of Nature Medicine, two reports by Jeong et al.3 and Jiang et al.4 show that the mammalian sirtuin Sirt1 can protect against mutant huntingtin neurotoxicity in three different mouse models of Huntington's disease. These studies provide new insights into the neuroprotective functions of sirtuins and may thus have important implications for the development of neurotherapeutics. Huntington's disease is a dominantly inherited neurodegenerative disorder characterized by uncontrolled movements, cognitive decline and psychiatric abnormalities. It is caused by the expansion of a CAG repeat in the gene encoding huntingtin, leading to the expression of huntingtin with expanded glutamine tracts5. Huntingtin bearing an expanded polyglutamine stretch adopts an altered conformation, resulting in protein aggregation. Huntington's disease is one of nine polyglutamine diseases that share this feature of aberrant proteostasis with a larger class of neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis. Several mouse models that recapitulate features of Huntington's disease have been generated by the transgenic expression of a severely truncated N-terminal huntingtin fragment or the full-length huntingtin protein. Jeong et al.3 focused on R6/2 mice, one of the truncation models, and crossed them to a brain-specific knockout (BSKO) of Sirt1 or a model in which Sirt1 was knocked in to the endogenous β-actin locus (Sirt1-KI). They found that BSKO-R6/2 mice suffered from a more severe neurodegenerative and neuropathological phenotype than R6/2 mice, but the Sirt1-KI–R6/2 mice showed the opposite outcome: an amelioration of neuronal atrophy and protein aggregation, accompanied by a 30% extension in survival. By comparison, Jiang et al.4 used a different truncation model, N171-82Q mice, and a full-length model in which huntingtin was expressed from a bacterial artificial chromosome (BAC-HD mice), and crossed each of these models with a different Sirt1 transgenic model from the one used by Jeong et al.3. They found that Sirt1 overexpression significantly attenuated motor phenotypes and reduced neuronal atrophy in both Huntington's models. Together, these two independent studies strongly support that Sirt1 expression is a powerful modifier of Huntington's disease phenotypes in transgenic mice. How does Sirt1 mediate neuroprotection in Huntington's disease? To answer this question, both groups considered brain-derived neurotrophic factor (BDNF), whose reduced expression has been strongly implicated in Huntington's disease striatal degeneration6. Jeong et al.3 identified BDNF using an expression array analysis of striatal samples from Sirt1-KI–R6/2 mice, leading them to perform a detailed analysis of BDNF transcription regulation. This work yielded evidence that Sirt1 transactivates BDNF expression at a promoter region that is also regulated by the cyclic AMP response element binding (CREB) transcription factor. This finding led Jeong et al.3 to investigate whether transducer of regulated CREB activity 1 (TORC1), a transcriptional coactivator known to enhance CREB function7 (not to be confused with the mTORC1 complex), is involved in Sirt1-mediated regulation of BDNF transcription. Through a comprehensive biochemical analysis, they determined that Sirt1-mediated deacetylation of TORC1 at certain lysine residues (particularly Lys13) promotes TORC1's interaction with CREB and that mutant huntingtin interferes with Sirt1 through a physical interaction that may be dependent on polyglutamine length3. Jiang et al.4 had previously implicated BDNF in the rescue of the Huntington's disease phenotype, prompting them to examine the BDNF receptor and discover that Sirt1 overexpression favored the phosphorylation and consequent activation of Trk-B, a neurotrophic tyrosine kinase. They also evaluated the effects of Foxo3a, which is a well-known Sirt1 target and candidate neuroprotective factor, and found that Sirt1 restoration of ATP production in cultured Huntington's disease striatal-like neurons depends upon Foxo3a, and that Foxo3a overexpression is linked to the recovery of BDNF and DARPP32 (a dopamine pathway protein) expression in Huntington's disease cells. Akin to Jeong et al.3, Jiang et al.4 also found that Sirt1 deacetylase activity is crucial for neuroprotection in the Huntington's disease cells, presumably via its activation of Foxo3a, although Sirt1 could also act on other targets, such as PGC-1α, for which a role in Huntington's disease pathogenesis is well established4. Thus, on the basis of these two studies, a model for Sirt1 dysfunction in Huntington's disease would include the following key elements: physical interaction of mutant huntingtin protein with Sirt1, inhibition of Sirt1 deacetylase activity, inactivation of Sirt1 downstream targets such as TORC1 and Foxo3a, and reduced expression of crucial neurotrophic factors and metabolic regulators (Fig. 1). The role of sirtuins in neurodegeneration has been heavily debated, and conflicting reports have argued that sirtuin activation or inhibition can be neuroprotective. This has even been the case in Huntington's disease, in which studies in Caenorhabditis elegans support a neuroprotective role for sirtuins but studies in Drosophila do not8, 9. In terms of mammalian relevance, Sirt1 activation in a mouse model with some features of Alzheimer's disease has been shown to be potentially neuroprotective10. However, the fact that sirtuins have diverse physiological roles and affect a range of metabolic processes confounds investigations with Sirt1 and its pharmacological activators. Many neurodegenerative disease models actually show non-neural phenotypes, including metabolic abnormalities. Indeed, small body size and reduced body weight have been observed in most mouse models for such disorders, and Huntington's disease mouse models also show perturbed glucose metabolism and insulin pathway regulation. As Sirt1 can elicit multiple divergent effects in the central nervous system and periphery, different outcomes might occur, depending on how, when and where Sirt1 is activated. A comparison of the work of Jeong et al.3 and Jiang et al.4 reveals that although the Sirt1-KI–R6/2 mice did not show increased body weight, Sirt1 overexpression in the BAC-HD mice attenuated weight loss and abnormal glucose regulation3, 4. Furthermore, there is a disconnect between the observed effects of Sirt1 on protein aggregation, with Sirt1 overexpression or knockout modulating inclusion formation in the brain of the R6/2 mice, but Sirt1 has no effect on aggregation in the N171-82Q mice. These findings underscore the complexity inherent in working with alternative Huntington's disease models and varying types of Sirt1 mouse models in which Sirt1 modulation is accomplished in different ways. Nonetheless, the two studies provide compelling support that Sirt1 has a neuroprotective effect in Huntington's disease, and they also raise important questions. Perhaps the most imperative issue is whether there are broader implications of Sirt1's neuroprotective effects for other neurodegenerative diseases. Jeong et al.3 and Jiang et al.4 propose that Sirt1 inhibition is driven by a physical interaction between mutant huntingtin and Sirt1. Of course, delineating the nature of this interaction, for example, whether it is direct or indirect, and why it occurs with normal huntingtin, will be important topics for future studies. But if only the Sirt1–mutant huntingtin interaction accounts for Sirt1 dysfunction, then Huntington's disease may represent a special case, and other neurodegenerative disorders may not be as affected by alterations in Sirt1, unless the mutated proteins responsible for those diseases also interact with Sirt1. Despite this caveat, Sirt1 deserves careful consideration as a therapeutic candidate based on the neuroprotective potency of its targets. Indeed, interfering with PGC-1α function may contribute to both Huntington's and Parkinson's diseases11, and Foxo3a can promote motor neuron survival when mutant neurodegenerative disease causing proteins are present12. Hence, although many questions remain about Sirt1 and other mammalian sirtuins, these two new studies suggest that sirtuins should receive even more attention, especially from investigators seeking treatments for neurodegenerative disorders. Download references