| Autor: |
Jeremy S. Francis, PhD, Ireneusz Wojtas, PhD, Vladimir Markov, MD, Steven J. Gray, PhD, Thomas J. McCown, PhD, R. Jude Samulski, PhD, Larissa T. Bilaniuk, MD, Dah-Jyuu Wang, PhD, Darryl C. De Vivo, MD, Christopher G. Janson, MD, Paola Leone, PhD |
| Jazyk: |
angličtina |
| Rok vydání: |
2016 |
| Předmět: |
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| Zdroj: |
Neurobiology of Disease, Vol 96, Iss , Pp 323-334 (2016) |
| Druh dokumentu: |
article |
| ISSN: |
1095-953X |
| DOI: |
10.1016/j.nbd.2016.10.001 |
| Popis: |
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. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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Full Text from ScienceDirect