N-acetylaspartate supports the energetic demands of developmental myelination via oligodendroglial aspartoacylase
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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.
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AAV/Olig001 can transduce neonatal oligodendrocytes in a mouse model of the congenital leukodystrophy Canavan disease, resulting in rescue of the congenital genetic defect and resistance to disease.
“We have previously shown AAV/Olig001 capable of transducing neonatal oligodendrocytes in a mouse model of the congenital leukodystrophy Canavan disease, resulting in rescue of the congenital genetic defect and resistance to disease.”
From Preclinical biodistribution, tropism, and efficacy of oligotropic AAV/Olig001 in a mouse model of congenital white matter disease (2021) · cites this paper as [4]
AAV/Olig001 tropism persists in adult brains of acutely symptomatic nur7 mice, despite using a constitutive CBh promoter active in all cell lineages.
“The present study extends previous observations of inherent oligotropism of AAV/Olig001 neonatal nur7 mice4 by showing that this tropism persists in adult brains of acutely symptomatic animals of the same strain, despite using a constitutive hybrid chicken β-actin promoter (CBh) promoter active in all cell lineages.”
From Preclinical biodistribution, tropism, and efficacy of oligotropic AAV/Olig001 in a mouse model of congenital white matter disease (2021) · cites this paper as [4]
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Francis, J. S., Markov, V., Wojtas, I. D., Gray, S., McCown, T., Samulski, R. J., Figueroa, M., & Leone, P. (2021) · Molecular Therapy - Methods & Clinical Development · doi:10.1016/j.omtm.2021.01.009 · Cited by 41 · see citing works
“We have previously shown AAV/Olig001 capable of transducing neonatal oligodendrocytes in a mouse model of the congenital leukodystrophy Canavan disease, resulting in rescue of the congenital genetic defect and resistance to disease.(4) This important proof of concept demonstrates the ability of AAV/Olig001 to reconsti…”
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Metovic, J., Li, Y., Gong, Y., & Eichler, F. (2024) · Neurotherapeutics · doi:10.1016/j.neurot.2024.e00443 · Cited by 16 · see citing works
- Authors
- Francis, J. S., Wojtas, I., Markov, V., Gray, S. J., McCown, T. J., Samulski, R. J., Bilaniuk, L. T., Wang, D.-J., De Vivo, D. C., Janson, C. G., & Leone, P.
- Affiliations
- Rowan University (US)
- University of North Carolina at Chapel Hill (US)
- Children's Hospital of Philadelphia (US)
- University of Illinois Chicago (US)
- Corresponding author
- Leone, Paola
- ORCID
- Venue
- Neurobiology of Disease
- Publisher
- Elsevier BV
- Published
- 2016-12
- Volume
- 96
- Pages
- 323-334
- ISSN
- 0969-9961 (ISSN-L)
- PMC
- PMC5102763
- OpenAlex
- W2528301714
- Cited by
- 49
- References
- 53
- Citations by year
- 2026: 7 · 2025: 5 · 2024: 7 · 2023: 2 · 2022: 3 · 2021: 8 · 2020: 5 · 2019: 2 · 2018: 5 · 2017: 3 · 2016: 2
- FWCI
- 3.91
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Neurobiology of Disease (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- UNC Libraries
- Funders
- Bamboo Therapeutics (15-0190)
- NIH (STTR#R41G044890-01A1, NS088763-01A1)
- Canavan Research Illinois
- Ralph & Lois Silver Foundation
- Jacob's Cure
- Michel J. Fox Foundation
- Research to Prevent Blindness
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
- Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
- Keywords
- N-acetylaspartate, aspartoacylase, Canavan disease, developmental myelination, oligodendrocytes, brain energy metabolism, acetyl-CoA, gene therapy, fatty acid synthesis, motor function, vacuolization, neurodegeneration
- MeSH terms
- Autophagy-Related Proteins, Dependovirus, Amidohydrolases, Animals, Aspartic Acid, Brain, Child, Child, Preschool, Myelin Basic Protein, Energy Metabolism, Female, Gene Expression Regulation, Humans, Infant, Male, Mice, Transgenic, Movement Disorders, Myelin Sheath, Oligodendroglia, Canavan Disease, Disease Progression, Neurodegenerative Diseases, Intracellular Signaling Peptides and Proteins, Green Fluorescent Proteins, Mice, Basic Helix-Loop-Helix Proteins, Basic Helix-Loop-Helix Transcription Factors, HEK293 Cells
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