Abstract
Canavan disease (CD) is a genetic degenerative brain disorder associated with mutations of the gene encoding aspartoacylase (ASPA). In humans, the CD syndrome is marked by early onset, hydrocephalus, macroencephaly, psychomotor retardation, and spongiform myelin sheath vacuolization with progressive leukodystrophy. Metabolic hallmarks of the disease include elevated N-acetylaspartate (NAA) levels in brain, plasma and CSF, along with daily excretion of large amounts of NAA and its anabolic metabolite, N-acetylaspartylglutamate (NAAG). Of the observed neuropathies, the most important appears to be the extensive demyelination that interferes with normal neuronal signaling. However, finding the links between the lacks of ASPA activity in oligodendrocytes, the buildup of NAA in white matter (WM) and the mechanisms underlying the edematous spongiform leukodystrophy have remained elusive. In this analytical review we consider what those links might be and propose that in CD, the pathological buildup of NAA in limited WM extracellular fluid (ECF) is responsible for increased ECF osmotic–hydrostatic pressure and initiation of the demyelination process. We also hypothesize that NAA is not directly liberated by neurons in WM as it is in gray matter, and that its source in WM ECF is solely as a product of the catabolism of axon-released NAAG at nodes of Ranvier by astrocyte NAAG peptidase after it has docked with the astrocyte surface metabotropic glutamate receptor 3. This hypothesis ascribes for the first time a possible key role played by astrocytes in CD, linking the lack of ASPA activity in myelinating oligodendrocytes, the pathological buildup of NAA in WM ECF, and the spongiform demyelination process. It also offers new perspectives on the cause of the leukodystrophy in CD, and on possible treatment strategies for this inherited metabolic disease.
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Abbreviations
- Ac:
-
Acetate
- AQP4:
-
Aquaporin 4
- Asp:
-
Aspartate
- ASPA:
-
Aspartoacylase
- atm:
-
Atmospheres
- CD:
-
Canavan disease
- CNS:
-
Central nervous system
- CSF:
-
Cerebrospinal fluid
- ECF:
-
Extracellular fluid
- ECS:
-
Extracellular space
- fMRS:
-
Functional magnetic resonance spectroscopy
- Glc:
-
Glucose
- Glu:
-
Glutamate
- GM:
-
Gray matter
- GRM3:
-
Metabotropic Glu receptor 3
- IND’s:
-
Investigative new drugs
- Me+ :
-
Monovalent metal cation
- MWP:
-
Molecular water pump
- NAA:
-
N-Acetylaspartate
- NAAG:
-
N-Acetylaspartylglutamate
- ODS:
-
Osmotic demyelination syndrome
- Pn:
-
Paranodal
- WM:
-
White matter
References
Kaya N, Imtiaz F, Colak D et al (2008) Genome-wide gene expression profiling and mutation analysis of Saudi patients with Canavan disease. Genet Med 10(9):675–684. doi:10.1097/GIM.0b013e31818337a8
Janson CG, McPhee SWJ, Francis J (2006) Natural history of Canavan disease revealed by proton magnetic resonance spectroscopy (1H-MRS) and diffusion-weighted MRI. Neuropediatrics 37:209–221
Baslow MH (2007) N-acetylaspartate and N-acetylaspartylglutamate. In: Lajtha A (ed) Handbook of neurochemistry and molecular neurobiology. Amino Acids and Peptides in the Nervous System, pp 418. 3rd edn, vol 6, Chap. 14. p305-346. Springer Science, NY ISBN:978-0-387-30342-0
Moffett JR, Ross B, Arun P et al (2007) N-acetylaspartate in the CNS: from neurodiagnostics to neurobiology. Prog Neurobiol 81:89–131. doi:10.1016/j.pneurobio.2006.12.003
Breitbach-Faller N, Schrader K, Rating D, Wunsch R (2003) Ultrasound findings in follow-up investigations in a case of aspartoacylase deficiency (Canavan disease). Neuropediat 34:96–99. doi:10.1055/s-2003-39601
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 75:453–459. doi:10.1046/j.1471-4159.2000.0750453.x
Baslow MH (2003) Brain N-acetylaspartate as a molecular water pump and its role in the etiology of Canavan disease. A mechanistic explanation. J Mol Neurosci 21:185–189. doi:10.1385/JMN:21:3:185
Horster F, Surtees R, Hoffmann GF (2005) Disorders of intermediary metabolism: toxic leukoencephalopathies. J Inherit Metab Dis 28(3):345–356. doi:10.1007/s10545-005-2164-5
Traka M, Wollmann RL, Cerda SR et al (2008) Nur7 is a nonsense mutation in the mouse aspartoacylase gene that causes spongy degeneration in the central nervous system. J Neurosci 28(45):11537–11549. doi:10.1523/JNEUROSCI.1490-08.2008
Namboodiri AMA, Moffett JR, Arun P et al (2006) Defective myelin lipid synthesis as a pathogenic mechanism of Canavan disease. Adv Exp Med Biol 576:145–163. doi:10.1007/0-387-30172-0_10
Chakraborty G, Mekala P, Yahya D, Wu G, Ledeen RW (2001) Intraneuronal N-acetylaspartate supplies acetyl groups for myelin lipid synthesis: evidence for myelin-associated aspartoacylase. J Neurochem 78:736–745. doi:10.1046/j.1471-4159.2001.00456.x
Mathew R, Arun P, Madhavarao CN, Moffett JR, Namboodiri MAA (2005) Progress toward acetate supplementation therapy for canavan disease: glyceryl triacetate administration increases acetate, but not N-acetylaspartate, levels in brain. J Pharmacol Exp Ther 315:297–303. doi:10.1124/jpet.105.087536
Ledeen RW, Wang J, Wu G, Lu Z-H, Chakraborty G, Meyenhofer M, Tyring SK, Matalon R (2006) Physiological role of N-acetylaspartate. Contribution to myelinogenesis. Chap 9 In: Adv Exp Med Biol, vol 576, pp 131–143. doi:10.1007/0-387-30172-0_9Springer pp. 375
Inglese M, Rusinek H, George IC, Babb JS, Grossman RI, Gonen O (2008) Global average gray and white matter N-acetylaspartate concentration in the human brain. Neuroimage 41:270–276
Baslow MH, Suckow R, Sapirstein V, Hungund BL (1999) Expression of aspartoacylase activity in cultured rat macroglial cells is limited to oligodendrocytes. J Mol Neurosci 13(1–2):47–53
Verkman AS, Binder DK, Bloch O et al (2006) Three distinct roles of aquaporin-4 in brain function revealed by knockout mice Biochim. Biophys Acta 1758(8):1085–1093
Tait MJ, Saadoun S, Bell BA, Papadopoulos MC (2008) Water movements in the brain: role of aquaporins. Trends in Neurosci 31(1):37–43
Sarchielli P, Tarducci R, Presciutti O et al (2005) Functional 1H-MRS findings in migraine patients with and without aura assessed interictally. Neuroimage 24:1025–1031
Baslow MH, Hrabe J, Guilfoyle DN (2007) Dynamic relationship between neurostimulation and N-acetylaspartate metabolism in the human visual cortex. Evidence that NAA functions as a molecular water pump during visual stimulation. J Mol Neurosci 32:235–245
Moffett JR, Namboodiri AMA (2006) Expression of N-acetylaspartate and N-acetylaspartylglutamate in the nervous system. Adv Exptl Med Biol 576:7–2621
Shah AJ, de la Flor R, Atkins A et al (2008) Development and application of a liquid chromatography/tandem mass spectrometric assay for measurement of N-acetylaspartate, N-acetylaspartylglutamate and glutamate in brain slice superfusates and tissue extracts. J Chromatography B 876(2):153–158
Hashemi M, Buibas M, Silva GA (2008) Automated detection of intercellular signaling in astrocyte networks using the converging squares algorithm J. Neurosci Methods 170:294–299
Baslow MH, Guilfoyle DN (2007) Using proton magnetic resonance imaging and spectroscopy to understand brain “activation”. Brain Lang 102(2):153–164
Xu H-L, Pelligrino DA (2007) ATP release and hydrolysis contribute to rat pial arteriolar dilatation elicited by neuronal activation. Exp Physiol 92:647–651
Baslow MH (2008) The astrocyte surface NAAG receptor and NAAG peptidase signaling complex as a therapeutic target. Drug News and Perspectives 21(5):251–257
Baslow MH (2009) A novel key-lock mechanism for inactivating amino acid neurotransmitters during transit across extracellular spaces. Amino Acids DOI 10.1007/s00726-009-0232-0 (Jan 17)
Woolley ML, Fricker A-C, Mok MHS et al (2008) Re-evaluation of N-acetylaspartylglutamate NAAG) as an agonist at group II mGluRs, and antagonist at NMDA receptors. Neuropharmacol 55:630 Abs. # 146
Fitzpatrick MO, Maxwell WL, Graham DI (1998) The role of the axolemma in the initiation of traumatically induced axonal injury. J Neurol Neurosurg Psychiatry 64:285–287
Upadhyay J, Hallock K, Dueros M et al (2008) Diffusion tensor spectroscopy and imaging of the arcuate fasciculus. Neuroimage 39:1–9
Sacha P, Zamecnik J, Barinka C et al (2007) Expression of glutamate carboxyeptidase II in human brain. Neurosci 2007(144):1361–1372
Lavreysen H, Dautzenberg FM (2008) Therapeutic potential of Group III metabotropic glutamate receptors. Curr Med Chem 15(7):671–684
Fotuhi M, Standaert DG, Testa CM et al (1994) Differential expression of metabotropic glutamate receptors in the hippocampus and entorhinal cortex of the rat. Mol. Br. Res. 21:283–292
Hinson SR, Pittock SJ, Lucchinetti CF, Roemer SF, Fryer JP, Kryzer TJ, Lennon VA (2007) Pathogenic potential of IgG binding to water channel extracellular domain in neuromyelitis optica. Neurology 69:2221–2231
Sartori S, Burlina AB, Salviati L et al (2008) Increased level of N-acetylaspartylglutamate (NAAG) in the CSF of a patient with Pelizaeus-Merzbacher-like disease due to a mutation in the GjA12 gene. Eur J Paed Neurol 12:348–350
Upadhyay J, Hallock K, Erb K et al (2007) Diffusion properties of NAA in human corpus callosum as studied with diffusion tensor spectroscopy. Mag Res Med 58:1045–1053
Halassa MM, Fellin T, Takano H (2007) Synaptic islands defined by the territory of a single astrocyte. J Neurosci 27(24):6473–6477
Hirano A, Dembitzer HM (1978) Morphology of normal central myelinated axons. In: Waxman SO (ed) Physiology and pathobiology of axons. Raven Press, NY, p 448
Neeb H, Zilles K, Shah NJ (2006) Fully-automated detection of cerebral water content changes: study of age- and gender-related H2O patterns with quantitative MRI. Neuroimage 29:910–922
Klugmann M, Symes CW, Klaussner BK et al (2003) Identification and distribution of aspartoacylase in postnatal rat brain. NeuroReport 14(14):1837–1840
Madhavarao CN, Moffett JR, Moore RA et al (2004) Immunohistochemical localization of aspartoacylase in the rat central nervous system. J Comp Neurol 472:318–329
Bitto E, Bingman CA, Wesenberg GE et al (2007) Structure of aspartoacylase, the brain enzyme impaired in Canavan disease. PNAS 104(2):456–461
Wang J, Matalon R, Bhatia G et al (2007) Bimodal occurrence of aspartoacylase in myelin and cytosol of brain. J Neurochem 101:448–457
Hershfield JR, Pattabiraman N, Madhavarao CN, Namboodiri MAA (2007) Mutational analysis of aspartoacylase: implications for Canavan disease. Brain Res 1148:1–14
Le Coq J, Pavlovsky A, Malik R et al (2008) Examination of the mechanism of human brain aspartoacylase through binding of an intermediate analogue. Biochem. 47(11):3484–3492
Guilfoyle DN, Suckow RF, Baslow MH (2003) The apparent dependence of the diffusion coefficient of N-acetylaspartate upon magnetic field strength: evidence of an interaction with NMR methodology. NMR in Biomed. 16(8):468–474
Laureno R, Karp BI (1997) Myelinolysis after correction of hyponatremia. Ann. Int. Med. 126(1):57–62
Tarhan NC, Agildere AM, Benli US et al (2004) Osmotic demyelination syndrome in end-stage renal disease after recent hemodialysis: MRI of the brain. AJR 182:809–816
Lien Y-HH (1995) Role of organic osmolytes in myeliolysis. A topographic study in rats after rapid correction of hyponatremia. J Clin Invest 95:1579–1586
Mehta SK, Kaur K, Sharma S, Bhasin KK (2007) Behavior of acetyl modified amino acids in reverse micelles: a non-invasive and physiochemical approach. J Colloid Interf Sci 314:689–698
Baslow MH, Guilfoyle DN (2002) Effect of N-acetylaspartic acid on the diffusion coefficient of water: a proton magnetic resonance phantom method for measurement of osmolyte-obligated water. Analyt. Biochem. 311(2):133–138
Valdez D, Le Huerou J-Y, Gindre M et al (2001) Hydration and protein folding in water and in reverse micelles: compressibility and volume changes. Biophys J 80:2751–2760
Thomas AG, Wozniak KM, Tsukamato T et al (2006) Glutamate carboxypeptidase II (NAALAdase) inhibition as a novel therapeutic strategy. Adv Exp Med Biol 576:327–337
Baslow MH (2001) Canavan’s spongiform leukodystrophy. A clinical anatomy of a genetic metabolic CNS disease. J Mol Neurosci 15:61–69
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CD, a rare genetic disorder that compromises a physiologically important tri-cellular brain metabolic system.
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Baslow, M.H., Guilfoyle, D.N. Are Astrocytes the Missing Link Between Lack of Brain Aspartoacylase Activity and the Spongiform Leukodystrophy in Canavan Disease?. Neurochem Res 34, 1523–1534 (2009). https://doi.org/10.1007/s11064-009-9958-z
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DOI: https://doi.org/10.1007/s11064-009-9958-z