N-Acetylaspartate Synthase Deficiency Corrects the Myelin Phenotype in a Canavan Disease Mouse Model But Does Not Affect Survival Time.
Canavan disease (CD) is a severe, lethal leukodystrophy caused by deficiency in aspartoacylase (ASPA), which hydrolyzes N-acetylaspartate (NAA). In the brains of CD patients, NAA accumulates to high millimolar concentrations. The pathology of the disease is characterized by loss of oligodendrocytes and spongy myelin degeneration in the CNS. Whether accumulating NAA, absence of NAA-derived acetate, or absence of any unknown functions of the ASPA enzyme is responsible for the pathology of the disease is not fully understood. We generated ASPA-deficient (Aspa(nur7/nur7)) mice that are also deficient for NAA synthase Nat8L (Nat8L(-/-)/Aspa(nur7/nur7)). These mice have no detectable NAA. Nevertheless, they exhibited normal myelin content, myelin sphingolipid composition, and full reversal of spongy myelin and axonal degeneration. Surprisingly, although pathology was fully reversed, the survival time of the mice was not prolonged. In contrast, Aspa(nur7/nur7) mice with only one intact Nat8L allele accumulated less NAA, developed a less severe pathology, phenotypic improvements, and, importantly, an almost normal survival time. Therefore, inhibition of NAA synthase is a promising therapeutic option for CD. The reduced survival rate of Nat8L(-/-)/Aspa(nur7/nur7) mice, however, indicates that complete inhibition of NAA synthase may bear unforeseeable risks for the patient. Furthermore, we demonstrate that acetate derived from NAA is not essential for myelin lipid synthesis and that loss of NAA-derived acetate does not cause the myelin phenotype of Aspa(nur7/nur7) mice. Our data clearly support the hypothesis that NAA accumulation is the major factor in the development of CD.
Institute of Biochemistry and Molecular Biology and.
Helena
H
Maier
Institute of Biochemistry and Molecular Biology and.
Lihua
L
Wang-Eckhardt
Institute of Anatomy, University of Bonn, 53115 Bonn, Germany, and.
Dieter
D
Hartmann
Institute of Biochemistry and Molecular Biology and Center for Rare Diseases, 53105 Bonn, Germany.
Volkmar
V
Gieselmann
Institute of Biochemistry and Molecular Biology and Center for Rare Diseases, 53105 Bonn, Germany eckhardt@uni-bonn.de.
Matthias
M
Eckhardt
D000123:Acetyltransferases / Q000235:genetics* / Q000378:metabolism; D000581:Amidohydrolases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001224:Aspartic Acid / Q000031:analogs & derivatives* / Q000378:metabolism; D001369:Axons / Q000473:pathology; D001522:Behavior, Animal; D017825:Canavan Disease / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D005260:Female; D005838:Genotype; D005911:Gliosis / Q000235:genetics / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009186:Myelin Sheath / Q000378:metabolism / Q000473:pathology*; D009410:Nerve Degeneration / Q000473:pathology; D013107:Sphingolipids / Q000378:metabolism; D016019:Survival Analysis
D004791:Enzyme Inhibitors; D013107:Sphingolipids; D001224:Aspartic Acid; C000179:N-acetylaspartate; D000123:Acetyltransferases; D000581:Amidohydrolases; C019751:aspartoacylase
Canavan disease; N-acetylaspartate; NAA synthase; aspartoacylase; leukodystrophy; spongy degeneration