title: N-acetylaspartate supports the energetic demands of developmental myelination via oligodendroglial aspartoacylase.
abstract: Breakdown of neuro-glial N-acetyl-aspartate (NAA) metabolism results in the failure of developmental myelination, manifest in the congenital pediatric leukodystrophy Canavan disease caused by mutations to the sole NAA catabolizing enzyme aspartoacylase. Canavan disease is a major point of focus for efforts to define NAA function, with available evidence suggesting NAA serves as an acetyl donor for fatty acid synthesis during myelination. Elevated NAA is a diagnostic hallmark of Canavan disease, which contrasts with a broad spectrum of alternative neurodegenerative contexts in which levels of NAA are inversely proportional to pathological progression. Recently generated data in the nur7 mouse model of Canavan disease suggests loss of aspartoacylase function results in compromised energetic integrity prior to oligodendrocyte death, abnormalities in myelin content, spongiform degeneration, and motor deficit. The present study utilized a next-generation "oligotropic" adeno-associated virus vector (AAV-Olig001) to quantitatively assess the impact of aspartoacylase reconstitution on developmental myelination. AAV-Olig001-aspartoacylase promoted normalization of NAA, increased bioavailable acetyl-CoA, and restored energetic balance within a window of postnatal development preceding gross histopathology and deteriorating motor function. Long-term effects included increased oligodendrocyte numbers, a global increase in myelination, reversal of vacuolation, and rescue of motor function. Effects on brain energy observed following AAV-Olig001-aspartoacylase gene therapy are shown to be consistent with a metabolic profile observed in mild cases of Canavan disease, implicating NAA in the maintenance of energetic integrity during myelination via oligodendroglial aspartoacylase.
authors.affiliation: Department of Cell Biology, Cell & Gene Therapy Center, Rowan School of Osteopathic Medicine, Stratford, NJ, USA.
authors.forename: Jeremy S
authors.initials: JS
authors.lastname: Francis
authors.affiliation: Department of Cell Biology, Cell & Gene Therapy Center, Rowan School of Osteopathic Medicine, Stratford, NJ, USA.
authors.forename: Ireneusz
authors.initials: I
authors.lastname: Wojtas
authors.affiliation: Department of Cell Biology, Cell & Gene Therapy Center, Rowan School of Osteopathic Medicine, Stratford, NJ, USA.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Markov
authors.affiliation: Department of Ophthalmology, UNC, Chapel Hill, NC, USA.
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Gray
authors.affiliation: Department of Psychiatry, UNC, Chapel Hill, NC, USA.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: McCown
authors.affiliation: Department of Pharmacology and Gene Therapy Center, UNC, Chapel Hill, NC, USA.
authors.forename: R Jude
authors.initials: RJ
authors.lastname: Samulski
authors.affiliation: Department of Radiology, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
authors.forename: Larissa T
authors.initials: LT
authors.lastname: Bilaniuk
authors.affiliation: Department of Radiology, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
authors.forename: Dah-Jyuu
authors.initials: DJ
authors.lastname: Wang
authors.affiliation: Department of Neurology, Columbia University, NY, USA.
authors.forename: Darryl C
authors.initials: DC
authors.lastname: De Vivo
authors.affiliation: Department of Neurology & Rehabilitation, University of Illinois at Chicago, Chicago, USA.
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Janson
authors.affiliation: Department of Cell Biology, Cell & Gene Therapy Center, Rowan School of Osteopathic Medicine, Stratford, NJ, USA. Electronic address: leonepa@rowan.edu.
authors.forename: Paola
authors.initials: P
authors.lastname: Leone
mesh_terms: D000581:Amidohydrolases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001224:Aspartic Acid / Q000031:analogs & derivatives* / Q000235:genetics / Q000378:metabolism; D000071183:Autophagy-Related Proteins; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D001921:Brain / Q000201:enzymology* / Q000473:pathology; D017825:Canavan Disease / Q000150:complications / Q000000981:diagnostic imaging / Q000235:genetics / Q000473:pathology*; D002648:Child; D002675:Child, Preschool; D000229:Dependovirus / Q000235:genetics; D018450:Disease Progression; D004734:Energy Metabolism / Q000235:genetics; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D007223:Infant; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009069:Movement Disorders / Q000209:etiology; D004676:Myelin Basic Protein / Q000378:metabolism; D009186:Myelin Sheath / Q000502:physiology*; D019636:Neurodegenerative Diseases / Q000209:etiology / Q000235:genetics; D009836:Oligodendroglia / Q000201:enzymology*
chemical_list: D000581:Amidohydrolases; D001224:Aspartic Acid; D000071183:Autophagy-Related Proteins; D051792:Basic Helix-Loop-Helix Proteins; D049452:Green Fluorescent Proteins; D047908:Intracellular Signaling Peptides and Proteins; D004676:Myelin Basic Protein; C494786:Olig1 protein, mouse; C428743:Rb1cc1 protein, mouse; C000179:N-acetylaspartate; C019751:aspartoacylase
keywords: Aspartoacylase; Canavan disease; Energy; Myelination; N-acetylaspartate