N-acetylaspartate supports the energetic demands of developmental myelination via oligodendroglial aspartoacylase

Jeremy S. Francis; Ireneusz Wojtas; Vladimir Markov; Steven J. Gray; Thomas J. McCown; R. Jude Samulski; Larissa T. Bilaniuk; Dah Jyuu Wang; Darryl C. De Vivo; Paola Leone

doi:10.1016/j.nbd.2016.10.001

N-acetylaspartate supports the energetic demands of developmental myelination via oligodendroglial aspartoacylase

Jeremy S. Francis, Ireneusz Wojtas, Vladimir Markov, Steven J. Gray, Thomas J. McCown, R. Jude Samulski, Larissa T. Bilaniuk, Dah Jyuu Wang, Darryl C. De Vivo, Paola Leone

Cell Biology

Rowan University

Research output: Contribution to journal › Article › peer-review

17 Scopus citations

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.

Original language	English (US)
Pages (from-to)	323-334
Number of pages	12
Journal	Neurobiology of Disease
Volume	96
DOIs	https://doi.org/10.1016/j.nbd.2016.10.001
State	Published - Dec 1 2016

All Science Journal Classification (ASJC) codes

Neurology

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10.1016/j.nbd.2016.10.001

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@article{9b02524e3b124c38a95eb80630456002,

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.",

author = "Francis, {Jeremy S.} and Ireneusz Wojtas and Vladimir Markov and Gray, {Steven J.} and McCown, {Thomas J.} and Samulski, {R. Jude} and Bilaniuk, {Larissa T.} and Wang, {Dah Jyuu} and {De Vivo}, {Darryl C.} and Paola Leone",

note = "Publisher Copyright: {\textcopyright} 2016",

year = "2016",

month = dec,

day = "1",

doi = "10.1016/j.nbd.2016.10.001",

language = "English (US)",

volume = "96",

pages = "323--334",

journal = "Neurobiology of Disease",

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T1 - N-acetylaspartate supports the energetic demands of developmental myelination via oligodendroglial aspartoacylase

AU - Francis, Jeremy S.

AU - Wojtas, Ireneusz

AU - Markov, Vladimir

AU - Gray, Steven J.

AU - McCown, Thomas J.

AU - Samulski, R. Jude

AU - Bilaniuk, Larissa T.

AU - Wang, Dah Jyuu

AU - De Vivo, Darryl C.

AU - Leone, Paola

PY - 2016/12/1

Y1 - 2016/12/1

N2 - 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.

AB - 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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DO - 10.1016/j.nbd.2016.10.001

M3 - Article

C2 - 27717881

SN - 0969-9961

VL - 96

SP - 323

EP - 334

JO - Neurobiology of Disease

JF - Neurobiology of Disease

ER -

N-acetylaspartate supports the energetic demands of developmental myelination via oligodendroglial aspartoacylase

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