Sirtuin Bests Huntingtin in Tug-of-War for Neural Survival

An excess of sirtuin one-ups mutant huntingtin in mice, saving neurons and delaying Huntington’s disease (HD), according to two reports in the December 18 Nature Medicine online. Extra Sirt1 reduced brain atrophy in three different HD mouse models. The deacetylase appears to act via brain-derived neurotrophic factor (BDNF), among other potential mediators. The authors suggest that specific activators of Sirt1 could potentially treat Huntington’s as well as other kinds of neurodegeneration. On the clinical side of HD news, researchers report the results of the TRACK-HD trial in the January Lancet Neurology. The paper, published online December 2, offers analysis of potential biomarkers for diagnosis and tracking of disease progression in symptomatic and asymptomatic people with the HD mutation. Magnetic resonance imaging of brain atrophy was most effective in differentiating people who had HD, were presymptomatic, or were healthy.

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

Comments

  1. This comprehensive and beautifully crafted study presents results from the longitudinal TRACK-HD trial of pre-manifest HD, which, like the complementary PREDICT-HD (Aylward et al., 2011; Paulsen et al., 2010; Biglan et al., 2009) study, is searching for Huntington's disease biomarkers for use in clinical trials. The results of both studies will have important implications for AD and PD as well. HD can serve as a model (Ross and Tabrizi, 2011; Walker, 2007) for these more common diseases, because it is caused by mutations in a single gene. Since the length of the CAG expansion predicts age of onset, predictive testing can determine the approximate time to onset of individuals who are expansion positive but without signs and symptoms sufficient to diagnose manifest disease ("pre-manifest" individuals).

    The TRACK-HD findings closely parallel recent results from PREDICT-HD. Both studies find that atrophy in caudate and putamen (corpus striatum of the basal ganglia) long precede diagnosable onset of HD, and that atrophy is measurable longitudinally even in the pre-manifest period. In addition, somewhat unexpectedly, both studies have found that subcortical white matter also is an excellent longitudinal biomarker.

    Consistent with the concept that HD is a disease prominently affecting the basal ganglia, which coordinate movement, thought, and emotion, both studies have found that all three functions are affected, and have measureable longitudinal change, though movement and cognition have more consistent change, which is detectible earlier. The particular contribution of TRACK-HD is to report all measures together in a clear and consistent fashion so that effect sizes can be compared. Rather than attempting to choose any single measure as pre-eminent, the TRACK-HD report suggests that several measures together may be most useful for future clinical trials.

    HD can provide many lessons for AD, PD, and other progressive brain diseases. In all these diseases, brain atrophy begins many years prior to onset of clinically diagnosable ("manifest") illness. Ideally, therapeutic interventions should also begin early. With appropriate biomarkers, treatments can be identified not just to slow progression of disease after it begins, but to delay—or even conceivably prevent—onset, thus addressing these devastating degenerative diseases with preventive therapy.

    References:

    Aylward EH, Liu D, Nopoulos PC, Ross CA, Pierson RK, Mills JA, Long JD, Paulsen JS, . Striatal Volume Contributes to the Prediction of Onset of Huntington Disease in Incident Cases. Biol Psychiatry. 2011 Sep 8; PubMed.

    Aylward EH, Nopoulos PC, Ross CA, Langbehn DR, Pierson RK, Mills JA, Johnson HJ, Magnotta VA, Juhl AR, Paulsen JS, . Longitudinal change in regional brain volumes in prodromal Huntington disease. J Neurol Neurosurg Psychiatry. 2011 Apr;82(4):405-10. PubMed.

    Biglan KM, Ross CA, Langbehn DR, Aylward EH, Stout JC, Queller S, Carlozzi NE, Duff K, Beglinger LJ, Paulsen JS, . Motor abnormalities in premanifest persons with Huntington's disease: the PREDICT-HD study. Mov Disord. 2009 Sep 15;24(12):1763-72. PubMed.

    Paulsen JS, Nopoulos PC, Aylward E, Ross CA, Johnson H, Magnotta VA, Juhl A, Pierson RK, Mills J, Langbehn D, Nance M, . Striatal and white matter predictors of estimated diagnosis for Huntington disease. Brain Res Bull. 2010 May 31;82(3-4):201-7. PubMed.

    Ross CA, Tabrizi SJ. Huntington's disease: from molecular pathogenesis to clinical treatment. Lancet Neurol. 2011 Jan;10(1):83-98. PubMed.

    Walker FO. Huntington's disease. Lancet. 2007 Jan 20;369(9557):218-28. PubMed.

    View all comments by Christopher A. Ross

  2. One of the major hurdles in the development of treatments for neurodegenerative
    diseases has been the absence of measurable indicators of disease progression.
    This is particularly important in diseases such as Huntington's, where pre-manifest subjects
    can be identified with a genetic test and potential treatments could be
    instituted many years before disease onset. The study by Tabrizi et al.
    demonstrates measurable disease-related changes over 24 months in pre-manifest
    and early manifest HD. Neuroimaging markers such as grey matter and white
    matter atrophy proved the most sensitive. There was also evidence of
    longitudinal cognitive decline in early HD. Importantly, the study suggests an
    association between the changes in brain atrophy and clinical progression.

    In
    comparison with an early HD group, where a range of potential outcomes to track
    disease progression were identified, striatal and total white matter atrophy
    appeared the most sensitive changes in pre-manifest subjects. It will be
    interesting to examine, as part of larger studies, to what extent these brain
    imaging changes correlate with disease progression in pre-manifest HD. Such
    trials will also provide the opportunity to assess reliability and validity of
    these findings across different sites and establish more definitely their
    potential as indicators of clinical progression. It is anticipated that the
    availability of such outcome measures may dramatically decrease the cost and
    duration of therapeutic trials in HD, and therefore allow for testing of a larger
    number of therapeutic agents identified in preclinical studies.

    View all comments by Dimitri Krainc

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References

News Citations

  1. Sirtuins’ Status Less Certain as Study Questions Longevity Effect
  2. Huntington Disease: Three Ways to Tackle Triplet Disorder
  3. Research Brief: SIRTs Keep Brain Minty Fresh
  4. New Insights and Strategies for Treating PolyQ Disorders
  5. Aging, Acetate, and Aβ: Sirtuins Regulate Metabolism and More
  6. Mitochondrial Mayhem—PGC-1α, Respiration, and Neurodegeneration

Paper Citations

  1. Burnett C, Valentini S, Cabreiro F, Goss M, Somogyvári M, Piper MD, Hoddinott M, Sutphin GL, Leko V, McElwee JJ, Vazquez-Manrique RP, Orfila AM, Ackerman D, Au C, Vinti G, Riesen M, Howard K, Neri C, Bedalov A, Kaeberlein M, Soti C, Partridge L, Gems D. Absence of effects of Sir2 overexpression on lifespan in C. elegans and Drosophila. Nature. 2011 Sep 22;477(7365):482-5. PubMed.
  2. Couzin-Frankel J. Genetics. Aging genes: the sirtuin story unravels. Science. 2011 Dec 2;334(6060):1194-8. PubMed.
  3. Parker JA, Arango M, Abderrahmane S, Lambert E, Tourette C, Catoire H, Néri C. Resveratrol rescues mutant polyglutamine cytotoxicity in nematode and mammalian neurons. Nat Genet. 2005 Apr;37(4):349-50. PubMed.
  4. Pallos J, Bodai L, Lukacsovich T, Purcell JM, Steffan JS, Thompson LM, Marsh JL. Inhibition of specific HDACs and sirtuins suppresses pathogenesis in a Drosophila model of Huntington's disease. Hum Mol Genet. 2008 Dec 1;17(23):3767-75. PubMed.
  5. Haigis MC, Guarente LP. Mammalian sirtuins--emerging roles in physiology, aging, and calorie restriction. Genes Dev. 2006 Nov 1;20(21):2913-21. PubMed.
  6. Donmez G, Wang D, Cohen DE, Guarente L. SIRT1 suppresses beta-amyloid production by activating the alpha-secretase gene ADAM10. Cell. 2010 Jul 23;142(2):320-32. PubMed. RETRACTED
  7. Duan W, Guo Z, Jiang H, Ware M, Li XJ, Mattson MP. Dietary restriction normalizes glucose metabolism and BDNF levels, slows disease progression, and increases survival in huntingtin mutant mice. Proc Natl Acad Sci U S A. 2003 Mar 4;100(5):2911-6. Epub 2003 Feb 14 PubMed.
  8. Qin W, Yang T, Ho L, Zhao Z, Wang J, Chen L, Zhao W, Thiyagarajan M, MacGrogan D, Rodgers JT, Puigserver P, Sadoshima J, Deng H, Pedrini S, Gandy S, Sauve AA, Pasinetti GM. Neuronal SIRT1 activation as a novel mechanism underlying the prevention of Alzheimer disease amyloid neuropathology by calorie restriction. J Biol Chem. 2006 Aug 4;281(31):21745-54. PubMed.
  9. Zuccato C, Cattaneo E. Brain-derived neurotrophic factor in neurodegenerative diseases. Nat Rev Neurol. 2009 Jun;5(6):311-22. PubMed.
  10. Bibb JA, Yan Z, Svenningsson P, Snyder GL, Pieribone VA, Horiuchi A, Nairn AC, Messer A, Greengard P. Severe deficiencies in dopamine signaling in presymptomatic Huntington's disease mice. Proc Natl Acad Sci U S A. 2000 Jun 6;97(12):6809-14. PubMed.
  11. Morris BJ. A forkhead in the road to longevity: the molecular basis of lifespan becomes clearer. J Hypertens. 2005 Jul;23(7):1285-309. PubMed.
  12. Mojsilovic-Petrovic J, Nedelsky N, Boccitto M, Mano I, Georgiades SN, Zhou W, Liu Y, Neve RL, Taylor JP, Driscoll M, Clardy J, Merry D, Kalb RG. FOXO3a is broadly neuroprotective in vitro and in vivo against insults implicated in motor neuron diseases. J Neurosci. 2009 Jun 24;29(25):8236-47. PubMed.
  13. Kim D, Nguyen MD, Dobbin MM, Fischer A, Sananbenesi F, Rodgers JT, Delalle I, Baur JA, Sui G, Armour SM, Puigserver P, Sinclair DA, Tsai LH. SIRT1 deacetylase protects against neurodegeneration in models for Alzheimer's disease and amyotrophic lateral sclerosis. EMBO J. 2007 Jul 11;26(13):3169-79. PubMed.
  14. Milne JC, Lambert PD, Schenk S, Carney DP, Smith JJ, Gagne DJ, Jin L, Boss O, Perni RB, Vu CB, Bemis JE, Xie R, Disch JS, Ng PY, Nunes JJ, Lynch AV, Yang H, Galonek H, Israelian K, Choy W, Iffland A, Lavu S, Medvedik O, Sinclair DA, Olefsky JM, Jirousek MR, Elliott PJ, Westphal CH. Small molecule activators of SIRT1 as therapeutics for the treatment of type 2 diabetes. Nature. 2007 Nov 29;450(7170):712-6. PubMed.

External Citations

  1. TRACK-HD
  2. PREDICT-HD

Further Reading

Papers

  1. Biglan KM, Ross CA, Langbehn DR, Aylward EH, Stout JC, Queller S, Carlozzi NE, Duff K, Beglinger LJ, Paulsen JS, . Motor abnormalities in premanifest persons with Huntington's disease: the PREDICT-HD study. Mov Disord. 2009 Sep 15;24(12):1763-72. PubMed.
  2. Klöppel S, Chu C, Tan GC, Draganski B, Johnson H, Paulsen JS, Kienzle W, Tabrizi SJ, Ashburner J, Frackowiak RS, . Automatic detection of preclinical neurodegeneration: presymptomatic Huntington disease. Neurology. 2009 Feb 3;72(5):426-31. PubMed.
  3. Bordone L, Guarente L. Calorie restriction, SIRT1 and metabolism: understanding longevity. Nat Rev Mol Cell Biol. 2005 Apr;6(4):298-305. PubMed.

Primary Papers

  1. Kieburtz K, Venuto C. TRACK-HD: both promise and disappointment. Lancet Neurol. 2012 Jan;11(1):24-5. PubMed.
  2. Tabrizi SJ, Reilmann R, Roos RA, Durr A, Leavitt B, Owen G, Jones R, Johnson H, Craufurd D, Hicks SL, Kennard C, Landwehrmeyer B, Stout JC, Borowsky B, Scahill RI, Frost C, Langbehn DR, . Potential endpoints for clinical trials in premanifest and early Huntington's disease in the TRACK-HD study: analysis of 24 month observational data. Lancet Neurol. 2012 Jan;11(1):42-53. PubMed.
  3. 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, Holtzman DM, Krainc D, Duan W. Neuroprotective role of Sirt1 in mammalian models of Huntington's disease through activation of multiple Sirt1 targets. Nat Med. 2012 Jan;18(1):153-8. PubMed.
  4. Jeong H, Cohen DE, Cui L, Supinski A, Savas JN, Mazzulli JR, Yates JR, Bordone L, Guarente L, Krainc D. Sirt1 mediates neuroprotection from mutant huntingtin by activation of the TORC1 and CREB transcriptional pathway. Nat Med. 2012 Jan;18(1):159-65. PubMed.

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