title: Aspartoacylase supports oxidative energy metabolism during myelination.
abstract: The inherited leukodystrophy Canavan disease arises due to a loss of the ability to catabolize N-acetylaspartic acid (NAA) in the brain and constitutes a major point of focus for efforts to define NAA function. Accumulation of noncatabolized NAA is diagnostic for Canavan disease, but contrasts with the abnormally low NAA associated with compromised neuronal integrity in a broad spectrum of other clinical conditions. Experimental evidence for NAA function supports a role in white matter lipid synthesis, but does not explain how both elevated and lowered NAA can be associated with pathology in the brain. We have undertaken a systematic analysis of postnatal development in a mouse model of Canavan disease that delineates development and pathology by identifying markers of oxidative stress preceding oligodendrocyte loss and dysmyelination. These data suggest a role for NAA in the maintenance of metabolic integrity in oligodendrocytes that may be of relevance to the strong association between NAA and neuronal viability. N-acetylaspartic acid is proposed here to support lipid synthesis and energy metabolism via the provision of substrate for both cellular processes during early postnatal development.
authors.affiliation: Cell and Gene Therapy Center, Department of Cell Biology, University of Medicine and Dentistry of NJ, Stratford, New Jersey 08084, USA. francijs@umdnj.edu
authors.forename: Jeremy S
authors.initials: JS
authors.lastname: Francis
authors.forename: Louise
authors.initials: L
authors.lastname: Strande
authors.forename: Vladamir
authors.initials: V
authors.lastname: Markov
authors.forename: Paola
authors.initials: P
authors.lastname: Leone
mesh_terms: D000581:Amidohydrolases / Q000378:metabolism*; D000818:Animals; D001224:Aspartic Acid / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D015415:Biomarkers; D017825:Canavan Disease / Q000201:enzymology / Q000378:metabolism; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid; D003711:Demyelinating Diseases / Q000378:metabolism / Q000473:pathology; D000229:Dependovirus / Q000235:genetics; D004734:Energy Metabolism / Q000502:physiology*; D005947:Glucose / Q000172:deficiency; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation / Q000502:physiology; D009186:Myelin Sheath / Q000502:physiology*; D009836:Oligodendroglia / Q000378:metabolism; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000502:physiology
chemical_list: D015415:Biomarkers; D001224:Aspartic Acid; C000179:N-acetylaspartate; D000581:Amidohydrolases; C019751:aspartoacylase; D005947:Glucose