Journal of Inherited Metabolic Disease

, Volume 37, Issue 3, pp 369–381 | Cite as

Dietary triheptanoin rescues oligodendrocyte loss, dysmyelination and motor function in the nur7 mouse model of Canavan disease

Original Article

Abstract

The inherited pediatric leukodystrophy Canavan disease is characterized by dysmyelination and severe spongiform degeneration, and is currently refractory to treatment. A definitive understanding of core disease mechanisms is lacking, but pathology is believed to result at least in part compromised fatty acid synthesis during myelination. Recent evidence generated in an animal model suggests that the breakdown of N-acetylaspartate metabolism in CD results in a heightened coupling of fatty acid synthesis to oligodendrocyte oxidative metabolism during the early stages of myelination, thereby causing acute oxidative stress. We present here the results of a dietary intervention designed to support oxidative integrity during developmental myelination in the nur7 mouse model of Canavan disease. Provision of the odd carbon triglyceride triheptanoin to neonatal nur7 mice reduced oxidative stress, promoted long-term oligodendrocyte survival, and increased myelin in the brain. Improvements in oligodendrocyte survival and myelination were associated with a highly significant reduction in spongiform degeneration and improved motor function in triheptanoin treated mice. Initiation of triheptanoin treatment in older animals resulted in markedly more modest effects on these same pathological indices, indicating a window of therapeutic intervention that corresponds with developmental myelination. These results support the targeting of oxidative integrity at early stages of Canavan disease, and provide a foundation for the clinical development of a non-invasive dietary triheptanoin treatment regimen.

Supplementary material

10545_2013_9663_Fig10_ESM.jpg (267 kb)
Suppl. Fig. 1

a) Distance traveled during open field activity at 8 weeks and 12 weeks. No significant differences between either wild type and nur7 controls, or nur7 triheptanoin treatment were observed. b) Ambulatory counts within the same open field activity session for the same animals, showing also no significant differences between any treatment or control groups. (JPEG 267 kb)

References

  1. Arun P, Madhavarao CN, Moffett JR et al (2010) Metabolic acetate therapy improves phenotype in the tremor rat model of Canavan disease. J Inherit Metab Dis 33:195–210PubMedCentralPubMedCrossRefGoogle Scholar
  2. Assadi M, Janson C, Wang DJ et al (2010) Lithium citrate reduces excessive intra-cerebral N-acetylaspartate in Canavan disease. Eur J Pediatr Neurol 14:354–359CrossRefGoogle Scholar
  3. Baslow MH (1999) Molecular water pumps and the aetiology of Canavan disease: a case of the sorcerer's apprentice. J Inherit Metab Dis 22:99–101Google Scholar
  4. Baslow MH (2000) Functions of N-acetyl-L-aspartate and N-acetyl-L-aspartylglutamate in the vertebrate brain: role in glial cell-specific signaling. J Neurochem 75:453–459Google Scholar
  5. Baslow MH, Guilfoyle DN (2013) Canavan Disease, a rare early-onset human spongiform leukodystrophy: insights into its genesis and possible clinical interventions. Biochimie 95:946–956PubMedCrossRefGoogle Scholar
  6. Bourre JM, Paturneau-Houas MY, Daudu OL, Baumann NA (1977) Lignoceric acid biosynthesis in the developing brain. Activities of mitochondrial acetyl-CoA-dependent synthesis and microsomal malonyl-CoA chain-elongating system in relation to myelination. Comparison between normal mouse and dysmyelinating mutants (quaking and jimpy). Eur J Biochem 72:41–47PubMedCrossRefGoogle Scholar
  7. Chakraborty G, Mekala P, Yahya D, Wu G, Ledeen RW (2001) Intraneuonal N-Acetylaspartate supplies actetyl groups for myelin lipid synthesis: evidence for myelin-associated aspartoacylase. J Neurochem 78:736–745PubMedCrossRefGoogle Scholar
  8. Clark JB (1998) N-acetyl aspartate: a marker for neuronal loss or mitochondrial dysfunction. Dev Neurosci 20:271–276Google Scholar
  9. D’Adamo AF, Gidez LI, Yatsu FM (1968) Acetyl transport mechanisms. Involvement of N-Acetyl aspartic acid in de novo fatty acid synthesis in the developing rat. Exp Brain Res 5:267–273PubMedGoogle Scholar
  10. Delaney SM, Geiger JD (1996) Brain regional levels of adenosine and adenosine nucleotides in rats killed by high-energy focused microwave irradiation. J Neurosci Methods 64:151–156Google Scholar
  11. Francis JS, Strande L, Markov V, Leone P (2012) Aspartoacylase supports oxidative energy metabolism during myelination. J Cereb Blood Flow Metab 32:1725–1736PubMedCentralPubMedCrossRefGoogle Scholar
  12. Fünfschilling U, Supplie LM, Mahad D et al (2012) Glycolytic oligodendrocytes maintain myelin and long-term axonal integrity. Nature 485:517–521PubMedCentralPubMedGoogle Scholar
  13. Hawkins RA, Williamson DH, Krebs HA (1971) Ketone-body utilization by adult and suckling rat brain in vivo. Biochem J 122:13–18PubMedCentralPubMedGoogle Scholar
  14. Huang W, Alexander GE, Chang L et al (2001) Brain metabolite concentration and dementia severity in Alzheimer’s disease: a (1)H MRS study. Neurology 57:626–632PubMedCrossRefGoogle Scholar
  15. Kaul R, Gao G-P, Balamurugan K, Matalon R (1993) Cloning of the human aspartoacylase cDNA and a common missense mutation in Canavan disease. Nat Genet 5:118–123PubMedCrossRefGoogle Scholar
  16. Kaul R, Gao GP, Aloya M, Balamurugan K, Petrosky A, Michals K, Matalon R (1994) Canavan disease: mutations among Jewish and non-Jewish patients. Am J Hum Genet 55:34–41PubMedCentralPubMedGoogle Scholar
  17. Kile BT, Henteges KE, Clark AT, Nakamura H, Salinger AP, Liu B, Box N, Stockton DW, Johnson RL, Behringer RR, Bradley A, Justice MJ (2003) Functional genetic analysis of mouse chromosome 11. Nature 425:81–86PubMedCrossRefGoogle Scholar
  18. Kitada K, Akimitsu T, Shigematsu Y, Kondo A, Maihara T, Yokoi N, Kuramoto T, Sasa M, Serikawa T (2000) Accumulation of Nacetyl-L-aspartate in the brain of the tremor rat, a mutant exhibiting absence-like seizure and spongiform degeneration in the central nervous system. J Neurochem 74:2512–2519Google Scholar
  19. Landis SC, Amara SG, Asadullah K, Austin CP, Blumenstein R, Bradley EW, Crystal RG et al (2012) A call for transparent reporting to optimize the predictive value of preclinical research. Nature 490:187–191PubMedCentralPubMedCrossRefGoogle Scholar
  20. Lazzarino G, Amorini AM, Fazzina G, Vagnozzi R, Signoretti S, Donzelli S, Di Stasio E, Giardina B, Tavazzi B (2003) Single sample preparation for simultaneous cellular redox and energy state determination. Anal Biochem 322:51–59PubMedCrossRefGoogle Scholar
  21. Lee Y, Morrison BM, Li Y et al (2012) Oligodendroglia metabolically support axons and contribute to neurodegeneration. Nature 487:443–448PubMedCentralPubMedCrossRefGoogle Scholar
  22. Leone P, Shera D, McPhee SW et al (2012) Long-term follow-up after gene therapy for Canavan disease. Sci Transl Med 4(165):165ra163PubMedCentralPubMedGoogle Scholar
  23. Madhavarao CN, Arun P, Moffett JR et al (2005) Defective N-acetylaspartate catabolism reduces brain acetate levels and myelin lipid synthesis in Canavan’s disease. Proc Natl Acad Sci U S A 102:5221–5226PubMedCentralPubMedCrossRefGoogle Scholar
  24. Madhavarao CN, Arun P, Anikster Y, Mog SR, Staretz-Chacham O, Moffett JR, Grundberg NE, Gahl WA, Namboodiri MA (2009) Glyceryl triacetate for Canavan disease: a low-dose trial in infants and evaluation of a higher dose for toxicity in the tremor rat model. J Inherit Metab Dis 32:640–650PubMedCrossRefGoogle Scholar
  25. Marin-Valencia I, Roe CR, Pascual JM (2010) Pyruvate carboxylase deficiency: mechanisms, mimics and anaplerosis. Mol Genet Metab 101:9–17PubMedCrossRefGoogle Scholar
  26. Marin-Valencia I, Good LB, Ma Q, Malloy CR, Pascual JM (2013) Heptanoate as a neural fuel: energetic and neurotransmitter: energetic and neurotransmitter precursors in mormal and glucose transporter-1 deficient (G1D) brain. J Cereb Blood Flow Metab 33:175–182PubMedCentralPubMedCrossRefGoogle Scholar
  27. Moore TJ, Lione AP, Sugden MC, Regeb DM (1976) Beta-hydroxybuturate transport in rat brain: developmental and dietary modifcations. Am J Physiol 230:619–630PubMedGoogle Scholar
  28. Moreno A, Ross BD, Bluml S (2001) Direct determination of the N-acetyl-L-aspartate synthesis rate in the human brain by (13)C MRS and [1-(13)C]glucose infusion. J Neurochem 77:347–350PubMedCrossRefGoogle Scholar
  29. Patel TB, Clark JB (1979) Synthesis of N-acetyl-L-aspartate by rat brain mitochondria and its involvement in mitochondrial/cytosolic carbon transport. Biochem J 184:539–546Google Scholar
  30. Roe CR, Mochel F (2006) Anaplerotic diet therapy in inherited metabolic disease: therapeutic potential. J Inherit Metab Dis 29:332–340PubMedCrossRefGoogle Scholar
  31. Saher G, Rudolphi F, Corthals K, Ruhwedel T, Schmidt KF, Löwel S, Dibaj P, Barrette B, Möbius W, Nave KA (2012) Therapy of Pelizaeus-Merzbacher disease in mice by feeding a cholesterol-enriched diet. Nat Med 18:1130–1135Google Scholar
  32. Segel R, Anikster Y, Zevin S, Steinberg A, Gahl WA, Fisher D, Startez-Chacham O, Zimran A, Altarescu G (2011) A safety trial of high dose glyceryl triacetate for Canavan disease. Mol Genet Metab 103:203–206PubMedCrossRefGoogle Scholar
  33. Signoretti S, Marmarou A, Tavazzi B, Lazzarino G, Beaumont A, Vagnozzi R (2001) N-Acetylaspartate reduction as a measure if injury severity and mitochondrial dysfunction following diffuse traumatic brain injury. J Neurotrauma 18:977–991PubMedCrossRefGoogle Scholar
  34. Solsona MD, Fernandez LL, Boquet EM, Andres JL (2012) Lithium citrate as treatment of Canavan disease. Clin Neuropharmacol 35:150–151PubMedCrossRefGoogle Scholar
  35. Suzuki A, Stern SA, Bozdagi O et al (2011) Astrocyte-neuron lactate transport is required for long-term memory formation. Cell 144:810–823PubMedCentralPubMedCrossRefGoogle Scholar
  36. Tavazzi B, Vagnozzi, Signoretti S, Amorini AM, Finocchiaro A, Cimatti M, Delfini R, Di Pietro V, Belli A, Lazzarino GP (2007) Temporal window of metabolic brain vulnerability to oxidative and nitrostriative stresses-Part II. Neurosurgery 61:390–406PubMedCrossRefGoogle Scholar
  37. Thomas NK, Willis S, Sweetman L, Borges K (2012) Triheptanoin in acute mouse seizure models. Epilespy Res 99:312–317CrossRefGoogle Scholar
  38. Traka M, Wollmann RL, Cerda SR, Dugas J, Barres BA, Popko B (2008) Nur7 is a nonsense mutation in the mouse aspartoacylase gene that causes spongy degeneration of the CNS. J Neurosci 28:11537–11549PubMedCentralPubMedCrossRefGoogle Scholar
  39. Vagnozzi R, Signioretti S, Tavazzi B et al (2005) Hypothesis of the postconcussive vulnerable brain: experimental evidence of its metabolic occurrence. Neurosurgery 57:164–171PubMedCrossRefGoogle Scholar
  40. Wang J, Leone P, Wu G et al (2009) Myelin lipid abnormalities in the aspartoacylase-deficient tremor rat. Neurochem Res 34:138–148PubMedCrossRefGoogle Scholar
  41. Webber RJ, Edmond J (1977) Utilization of L(+)-3-hydroxybutyrate, D(−)-3-hydroxybutyrate, acetoacetate, and glucose for respiration and lipid synthesis in the 18-day-old rat. J Biol Chem 252:5222–5226PubMedGoogle Scholar
  42. Willis S, Stoll J, Sweetman L, Borges K (2010) Anticonvulsant effects of a triheptanoin diet in two mouse chronic seizure models. Neurobiol Dis 40:565–572PubMedCentralPubMedCrossRefGoogle Scholar

Copyright information

© SSIEM and Springer Science+Business Media Dordrecht 2013

Authors and Affiliations

  • Jeremy S. Francis
    • 1
  • Vladimir Markov
    • 1
  • Paola Leone
    • 1
  1. 1.Cell and Gene Therapy Center, Department of Cell BiologyRowan University School of Osteopathic MedicineStratfordUSA

Personalised recommendations