The Pathogenesis Of, and Pharmacological Treatment For, Canavan Disease

Overview

Journal Drug Discov Today

Specialty Pharmacology

Date 2022 May 31

PMID 35636725

Authors

Huijun Wei

John R Moffett

Man Amanat

Ali Fatemi

Takashi Tsukamoto

Aryan M Namboodiri

Barbara S Slusher

Affiliations

Soon will be listed here.

Abstract

Canavan disease (CD) is an inherited leukodystrophy resulting from mutations in the gene encoding aspartoacylase (ASPA). ASPA is highly expressed in oligodendrocytes and catalyzes the cleavage of N-acetylaspartate (NAA) to produce aspartate and acetate. In this review, we examine the pathologies and clinical presentation in CD, the metabolism and transportation of NAA in the brain, and the hypothetical mechanisms whereby ASPA deficiency results in dysmyelination and a failure of normal brain development. We also discuss therapeutic options that could be used for the treatment of CD.

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References

Taylor D, Davies S, Obrenovitch T, Urenjak J, Richards D, Clark J . Extracellular N-acetylaspartate in the rat brain: in vivo determination of basal levels and changes evoked by high K+. J Neurochem. 1994; 62(6):2349-55. DOI: 10.1046/j.1471-4159.1994.62062349.x. View

Arun P, Moffett J, Namboodiri A . Evidence for mitochondrial and cytoplasmic N-acetylaspartate synthesis in SH-SY5Y neuroblastoma cells. Neurochem Int. 2009; 55(4):219-25. DOI: 10.1016/j.neuint.2009.03.003. View

Lotun A, Gessler D, Gao G . Canavan Disease as a Model for Gene Therapy-Mediated Myelin Repair. Front Cell Neurosci. 2021; 15:661928. PMC: 8102781. DOI: 10.3389/fncel.2021.661928. View

Ahmed S, Li H, Cao C, Sikoglu E, Denninger A, Su Q . A single intravenous rAAV injection as late as P20 achieves efficacious and sustained CNS Gene therapy in Canavan mice. Mol Ther. 2013; 21(12):2136-47. PMC: 3863789. DOI: 10.1038/mt.2013.138. View

Copray S, Huynh J, Sher F, Casaccia-Bonnefil P, Boddeke E . Epigenetic mechanisms facilitating oligodendrocyte development, maturation, and aging. Glia. 2009; 57(15):1579-87. PMC: 2760733. DOI: 10.1002/glia.20881. View

Huber K, Hofer D, Trefely S, Pelzmann H, Madreiter-Sokolowski C, Duta-Mare M . N-acetylaspartate pathway is nutrient responsive and coordinates lipid and energy metabolism in brown adipocytes. Biochim Biophys Acta Mol Cell Res. 2019; 1866(3):337-348. PMC: 6390944. DOI: 10.1016/j.bbamcr.2018.08.017. View

Moffett J, Puthillathu N, Vengilote R, Jaworski D, Namboodiri A . Acetate Revisited: A Key Biomolecule at the Nexus of Metabolism, Epigenetics, and Oncogenesis - Part 2: Acetate and ACSS2 in Health and Disease. Front Physiol. 2020; 11:580171. PMC: 7693462. DOI: 10.3389/fphys.2020.580171. View

Nuri Sener R . Canavan disease: diffusion magnetic resonance imaging findings. J Comput Assist Tomogr. 2003; 27(1):30-3. DOI: 10.1097/00004728-200301000-00006. View

Surendran S . Upregulation of N-acetylaspartic acid resulting nitric oxide toxicity induces aspartoacylase mutations and protein interaction to cause pathophysiology seen in Canavan disease. Med Hypotheses. 2010; 75(6):533-4. DOI: 10.1016/j.mehy.2010.07.017. View

10.

Taylor D, Davies S, Obrenovitch T, Doheny M, Patsalos P, Clark J . Investigation into the role of N-acetylaspartate in cerebral osmoregulation. J Neurochem. 1995; 65(1):275-81. DOI: 10.1046/j.1471-4159.1995.65010275.x. View

11.

Tacke U, Olbrich H, Sass J, Fekete A, Horvath J, Ziyeh S . Possible genotype-phenotype correlations in children with mild clinical course of Canavan disease. Neuropediatrics. 2005; 36(4):252-5. DOI: 10.1055/s-2005-865865. View

12.

Adachi M, Schneck L, Cara J, VOLK B . Spongy degeneration of the central nervous system (van Bogaert and Bertrand type; Canavan's disease). A review. Hum Pathol. 1973; 4(3):331-47. DOI: 10.1016/s0046-8177(73)80098-x. View

13.

Wiame E, Tyteca D, Pierrot N, Collard F, Amyere M, Noel G . Molecular identification of aspartate N-acetyltransferase and its mutation in hypoacetylaspartia. Biochem J. 2009; 425(1):127-36. DOI: 10.1042/BJ20091024. View

14.

Ishiyama G, Lopez I, Baloh R, Ishiyama A . Canavan's leukodystrophy is associated with defects in cochlear neurodevelopment and deafness. Neurology. 2003; 60(10):1702-4. DOI: 10.1212/01.wnl.0000065893.60879.d3. View

15.

Toft P, Rolland M, Pryds O, Muller-Forell W, Christensen E, Lehnert W . Magnetic resonance imaging in juvenile Canavan disease. Eur J Pediatr. 1993; 152(9):750-3. DOI: 10.1007/BF01953994. View

16.

Baslow M . Brain N-acetylaspartate as a molecular water pump and its role in the etiology of Canavan disease: a mechanistic explanation. J Mol Neurosci. 2003; 21(3):185-90. DOI: 10.1385/jmn:21:3:185. View

17.

Bogner-Strauss J . -Acetylaspartate Metabolism Outside the Brain: Lipogenesis, Histone Acetylation, and Cancer. Front Endocrinol (Lausanne). 2017; 8:240. PMC: 5611401. DOI: 10.3389/fendo.2017.00240. View

18.

Pederzolli C, Mescka C, Scapin F, Rockenbach F, Sgaravatti A, Sgarbi M . N-acetylaspartic acid promotes oxidative stress in cerebral cortex of rats. Int J Dev Neurosci. 2007; 25(5):317-24. DOI: 10.1016/j.ijdevneu.2007.04.002. View

19.

Singhal N, Huang H, Li S, Clements R, Gadd J, Daniels A . The neuronal metabolite NAA regulates histone H3 methylation in oligodendrocytes and myelin lipid composition. Exp Brain Res. 2016; 235(1):279-292. PMC: 5875422. DOI: 10.1007/s00221-016-4789-z. View

20.

Baslow M . Canavan's spongiform leukodystrophy: a clinical anatomy of a genetic metabolic CNS disease. J Mol Neurosci. 2001; 15(2):61-9. DOI: 10.1385/JMN:15:2:61. View