Sorting Sirtuin’s Story
Sirt1 deacetylates a variety of targets, including histones and transcription factors. It is one in a family of proteins called sirtuins, which have been mired in controversy lately, with recent data failing to back up earlier claims that these enzymes promote longevity in animals (see ARF related news story on Burnett et al., 2011; Couzin-Frankel, 2011). In the course of that debate, “the data highlighting the therapeutic potential of Sirt1 activation in neurodegenerative disease have been somehow overlooked,” wrote Christian Neri of INSERM in Paris, France, who was not involved in the Nature Medicine papers, in an e-mail to ARF. The new papers put the neuroprotective aspect of sirtuins front and center.

In so doing, they also address another “mini-controversy” stemming from conflicting data on sirtuins and neural support, commented Rajiv Ratan of the Burke Medical Research Institute in New York, who was also not part of the current work. While sirtuin activation was reported to block toxicity of polyglutamines in nematode worms (see ARF related news story on Parker et al., 2005), inhibiting sirtuins appeared to prevent disease in a fruit fly model of Huntington’s disease (Pallos et al., 2008). Now, the back-to-back publications reporting a triad of mammalian models where Sirt1 is protective should help settle the question, Ratan said.

Leonard Guarente of MIT, a co-senior author on one of the new papers, was inspired by cell culture studies suggesting sirtuins could block neurodegeneration (reviewed in Haigis and Guarente, 2006). “We have been wondering for about 10 years now how important mammalian sirtuins were in aging and disease,” he said. To find out, he crossed mice overexpressing Sirt1 with models for each of Alzheimer’s, Parkinson’s, and Huntington’s diseases to create double transgenics. The Alzheimer’s results, in which Sirt1 was indeed protective, were published in 2010 (see ARF related news story on Donmez et al., 2010), and the Parkinson’s data are forthcoming, Guarente said.

For the Huntington’s studies, Guarente and co-first author Dena Cohen collaborated with study leader Dimitri Krainc of Massachusetts General Hospital in Boston. Krainc is also a coauthor on the second Nature Medicine paper. That work was led by Wenzhen Duan at Johns Hopkins University in Baltimore. Duan previously discovered that caloric restriction was protective in Huntington’s mice (see ARF related news story on Duan et al., 2003), and since sirtuins have been linked to the benefits of restricted diets (see ARF related news story on Qin et al., 2006), she suspected Sirt1 would mediate this protection. Both teams crossed the Sirt1-overexpressers with HD model mice, to discover that extra Sirt1 diminished striatal atrophy, which is normally observed in HD mice and in people with the disease. Depending on the model used, Sirt1 overexpression also delayed disease onset, extended survival, and reduced aggregation of mutant huntingtin protein.

Co-first author Hyunkyung Jeong from Krainc's lab, pursued the mechanism of Sirt1 protection in primary cortical neuron cultures. She discovered a novel target of Sirt1 in the central nervous system--the brain-specific co-activator TORC1. This protein works with the transcription factor CREB to activate various genes including PGC-1alpha and BDNF, which have been previously linked to HD (see ARF related news story and review by Zuccato and Cattaneo, 2009). Specifically, Krainc’s team proposed a model in which Sirt1 deacetylates TORC1, leading to its activation under physiological conditions. Jeong also found that mutant huntingtin inhibits the acetylase activity of its Sirt1 and blocks the CREB-TORC1 interaction.

The researchers found that in cells and in animal models overexpressing Sirt1 partially restored TORC1 function and bumped up BDNF and PGC-1alpha production. Guarente hypothesized that there is a molecular “tug-of-war” going on, with TORC1 caught between Sirt1 and mutant huntingtin. Ratan noted he would like to see this mechanism confirmed in vivo.

At Johns Hopkins, co-first authors Mali Jiang and Jiawei Wang (who has since moved to Beijing Friendship Hospital, China) addressed the potential protective roles of Sirt1 effectors including BDNF; DARP32, a member of the dopamine signaling cascade that HD model mice cannot regulate (Bibb et al., 2000); and the transcription factor and neurotrophin Foxo3a, known to be a Sirt1 substrate (Morris, 2005; Mojsilovic-Petrovic et al., 2009). Mutant huntingtin diminished BDNF and DARP32 protein levels in the Huntington’s mice, but Sirt1 overexpression restored the concentrations of these proteins. Similarly, Foxo3a exhibited subnormal acetylation in HD mouse brains, but returned to the regular amount in the double transgenics with excess Sirt1.

Various molecules downstream of Sirt1—in particular Foxo3a, TORC1, and PGC-1-α—make “a nice working list of high-priority therapy targets to develop,” said Albert La Spada of the University of California, San Diego. Ratan added that manipulating Sirt1, the master switch, could also be a solid approach to Huntington’s therapeutics.

A Sirt1-based treatment might be good for more than just Huntington’s. Others found that the deacetylase protects in models of amyotrophic lateral sclerosis as well as Alzheimer’s (Kim et al., 2007). Guarente suspects there may be a general mechanism that works in many neurodegenerative conditions, and is now searching for that kind of pathway. While researchers have come up with sirtuin activators (Milne et al., 2007), most are not specific for Sirt1 and do not readily cross the blood-brain barrier, Krainc said. The researchers stand ready to try out better Sirt1 activators in their mice, Guarente said.

A Cornucopia of Trial Tests
Should those compounds look promising, researchers will be looking for the best methods to test their efficacy in people, and that is where TRACK-HD comes in. “One of the major hurdles in the development of treatments for neurodegenerative disease has been the absence of measurable indicators of disease progression,” Krainc wrote in an e-mail to ARF). “This is particularly important in diseases such as HD, where pre-manifest subjects can be identified with a genetic test and potential treatments could be instituted many years before disease onset,” he suggested. Krainc was not part of the TRACK-HD study.

The multisite TRACK-HD team investigated a number of potential biomarkers over two years in three groups of people: those who had HD; those who carried the mutant gene, but were not yet sick; and healthy controls. Sarah Tabrizi of University College London, England, is first author on the Lancet Neurology report. Tabrizi and colleagues found that atrophy of the entire brain, as well as specific loss in the grey matter, white matter, and striatum, was a sensitive indicator of progression in both people with HD and those who were approaching symptom onset. In finger-tapping speed tests, the variability in asymptomatic HD mutation carriers was also a good measure. The results are consistent with those in the recent PREDICT-HD trial seeking markers of upcoming disease, noted Christopher Ross of Johns Hopkins University in an e-mail to ARF. Ross was not involved in the TRACK-HD study, although he coauthored the Duan paper. “The particular contribution of TRACK-HD is to report all measures together in a clear and consistent fashion,” he wrote. It “suggests that several measures together may be most useful for future clinical trials.”

However, Karl Kieburtz and Charles Venuto of the University of Rochester, New York, registered some disappointment in a Lancet Neurology commentary. “None of the new clinical measures seemed to outperform…the standard [Unified Huntington’s Disease Rating Scale] in individuals at risk for or with early HD,” they wrote. “More sensitive methods are still needed.” With better measures, researchers should be able to conduct smaller, faster trials, they wrote.—Amber Dance.

References:
Jeong H, Cohen DE, Cui L, Supinski A, Savas JN, Mazzulli JR, Yates JR 3rd, Bordone L, Guarente LP, Krainc D. Sirt1 mediates neuroprotection from mutant huntingtin by activation of the TORC1 and CREB transcriptional pathway. Nat Med. 2011 Dec 18. Abstract

Jiang M, Wang J, Fu J, Du L, Jeong H, West T, Xiang L, Peng Q, Hou Z, Cai H, Seredenina T, Arbez N, Zhu S, Sommers K, Qian J, Zhang J, Mori S, Yang XW, Tamashiro KL, Aja S, Moran TH, Luthi-Carter R, Martin B, Maudsley S, Mattson MP, Cichewicz RH, Ross CA, Holtzmann DM, Krainc D, Duan W. Neuroprotective role of Sirt1 in mammalian models of Huntington's disease through activation of multiple Sirt1 targets. Nat Med. 2011 Dec 18. Abstract

Tabrizi SJ, Reilmann R, Roos RA, Durr A, Leavitt B, Owen G, Jones R, Johnson H, Crawfurd D, Hicks SL, Kennard C, Landwermeyer B, Stout JC, Borowsky B, Scahill RI, Frost C, Langbehn DR, and the TRACK-HD investigators. Potential endpoints for clinical trials in premanifest and early Huntingtin’s disease in the TRACK-HD study: analysis of 24 month observational data. Lancet Neurol. 2012 Jan;11(1):42-53. Abstract

Kieburtz K, Venuto C. TRACK-HD: both promise and disappointment. Lancet Neurol. 2012 Jan;11(1):24-5. Abstract