title: Defective N-acetylaspartate catabolism reduces brain acetate levels and myelin lipid synthesis in Canavan's disease.
abstract: Canavan's disease (CD) is a fatal, hereditary disorder of CNS development that has been linked to mutations in the gene for the enzyme aspartoacylase (ASPA) (EC 3.5.1.15). ASPA acts to hydrolyze N-acetylaspartate (NAA) into l-aspartate and acetate, but the connection between ASPA deficiency and the failure of proper CNS development is unclear. We hypothesize that one function of ASPA is to provide acetate for the increased lipid synthesis that occurs during postnatal CNS myelination. The gene encoding ASPA has been inactivated in the mouse model of CD, and here we show significant decreases in the synthesis of six classes of myelin-associated lipids, as well as reduced acetate levels, in the brains of these mice at the time of peak postnatal CNS myelination. Analysis of the lipid content of white matter from a human CD patient showed decreased cerebroside and sulfatide relative to normal white matter. These results demonstrate that myelin lipid synthesis is significantly compromised in CD and provide direct evidence that defective myelin synthesis, resulting from a deficiency of NAA-derived acetate, is involved in the pathogenesis of CD.
authors.affiliation: Department of Anatomy, Physiology, and Genetics, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814, USA.
authors.forename: Chikkathur N
authors.initials: CN
authors.lastname: Madhavarao
authors.forename: Peethambaran
authors.initials: P
authors.lastname: Arun
authors.forename: John R
authors.initials: JR
authors.lastname: Moffett
authors.forename: Sylvia
authors.initials: S
authors.lastname: Szucs
authors.forename: Sankar
authors.initials: S
authors.lastname: Surendran
authors.forename: Reuben
authors.initials: R
authors.lastname: Matalon
authors.forename: James
authors.initials: J
authors.lastname: Garbern
authors.forename: Diana
authors.initials: D
authors.lastname: Hristova
authors.forename: Anne
authors.initials: A
authors.lastname: Johnson
authors.forename: Wei
authors.initials: W
authors.lastname: Jiang
authors.forename: M A Aryan
authors.initials: MA
authors.lastname: Namboodiri
mesh_terms: D019342:Acetic Acid / Q000378:metabolism*; D000581:Amidohydrolases / Q000172:deficiency / Q000235:genetics; D000818:Animals; D001224:Aspartic Acid / Q000031:analogs & derivatives* / Q000378:metabolism*; D001483:Base Sequence; D001921:Brain / Q000378:metabolism*; D017825:Canavan Disease / Q000235:genetics / Q000378:metabolism*; D004247:DNA / Q000235:genetics; D006801:Humans; D008055:Lipids / Q000096:biosynthesis*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008959:Models, Neurological; D009186:Myelin Sheath / Q000378:metabolism; D051381:Rats
chemical_list: D008055:Lipids; D001224:Aspartic Acid; D004247:DNA; C000179:N-acetylaspartate; D000581:Amidohydrolases; C019751:aspartoacylase; D019342:Acetic Acid