Acetyl transport mechanisms. Involvement of N-Acetyl aspartic acid in de novo fatty acid biosynthesis in the developing rat brain

D’Adamo, Amedeo F.; Gidez, Lewis I.; Yatsu, Frank M.

doi:10.1007/bf00235902

Cited by 119 publications

(59 citation statements)

References 22 publications

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“…24 However, its function remains unknown, although one suggestion is that NAA donates its acetyl group for lipid synthesis, particularly during the developmental period corresponding to the myelination of neurons. 25,26 The NAA level was very low in some areas of glioblastoma that showed loss of neurons and axons, and was not detected in the glioblastoma center, where neurons were not present.…”

Section: Neuroectodermal Tumor (Glioma)mentioning

confidence: 99%

Absolute concentrations of metabolites in human brain tumors usingin vitro proton magnetic resonance spectroscopy

1997

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Section: Neuroectodermal Tumor (Glioma)mentioning

confidence: 99%

Absolute concentrations of metabolites in human brain tumors usingin vitro proton magnetic resonance spectroscopy

1997

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“…It was observed in neurons and oligodendrocytes (Urenjak et al, 1992(Urenjak et al, , 1993. The substance seems to be involved in fatty acid synthesis, in acetylation of aspartyl RNA, in stabilization of the cellular acetylCoA pool or in storage of aspartate (D'Adamo et al, 1968;Burri et al, 1991). A complete understanding of its role in cerebral metabolism is not yet reached (Birken and Oldendorf, 1989;Miller, 1991), but there is increasing evidence that NAA is a neuronal marker and that NAA reductions indicate neuronal cell loss and degeneration Graham et al, 1994).…”

Section: Magnetic Resonance Spectroscopy and Cerebral Metabolitesmentioning

confidence: 99%

Proton Magnetic Resonance Spectroscopy in Dementia of Alzheimer Type

Heun¹,

Schlegel²,

Graf-Morgenstern³

et al. 1997

Int. J. Geriat. Psychiatry

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“…In particular, the levels of NAA, ASPA, and Asp-NAT rise with a temporal course similar to those of myelin proteins (18,19). Further, it has been shown that NAA contributes acetyl groups for the synthesis of lipids, which in turn are incorporated into myelin (20,21).…”

mentioning

confidence: 97%

Defective N-acetylaspartate catabolism reduces brain acetate levels and myelin lipid synthesis in Canavan's disease

Madhavarao

Arun

Moffett

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

170

153

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Canavan's disease (CD) is a fatal, hereditary disorder of CNS development that has been linked to mutations in the gene for the enzyme aspartoacylase (ASPA) (EC 3.5.1.15). ASPA acts to hydrolyze N-acetylaspartate (NAA) into L-aspartate and acetate, but the connection between ASPA deficiency and the failure of proper CNS development is unclear. We hypothesize that one function of ASPA is to provide acetate for the increased lipid synthesis that occurs during postnatal CNS myelination. The gene encoding ASPA has been inactivated in the mouse model of CD, and here we show significant decreases in the synthesis of six classes of myelinassociated lipids, as well as reduced acetate levels, in the brains of these mice at the time of peak postnatal CNS myelination. Analysis of the lipid content of white matter from a human CD patient showed decreased cerebroside and sulfatide relative to normal white matter. These results demonstrate that myelin lipid synthesis is significantly compromised in CD and provide direct evidence that defective myelin synthesis, resulting from a deficiency of NAAderived acetate, is involved in the pathogenesis of CD.acetyl CoA ͉ leukodystrophy ͉ oligodendrocytes ͉ aspartoacylase N -acetylaspartate (NAA) attains one of the highest concentrations of any molecule in the human CNS (1), yet the functions it serves remain controversial. NAA is synthesized from L-aspartate and acetyl CoA in neuronal mitochondria by the enzyme aspartate N-acetyltransferase (Asp-NAT) (EC 2.3.1.17) (2, 3). NAA is found predominantly in neurons, (4) but the catabolic enzyme aspartoacylase (ASPA) is present primarily in oligodendrocytes in the CNS (5). The high concentration of NAA in the CNS and its characteristic peak in water-suppressed proton magnetic resonance spectroscopy (MRS) permits noninvasive determinations of NAA concentrations in the human brain. MRS determinations of NAA levels are commonly used for evaluating the integrity of neurons in a number of neurological disorders, and this method has emerged as a preferred technique for following the clinical course of several CNS pathologies (6-8). MRS studies operate on the assumptions that NAA is synthesized by and accumulated in neurons and that the steady-state NAA levels in the brain can be interpreted as indicating overall neuronal health or integrity (9, 10).Canavan's disease (CD) is a fatal, hereditary leukodystrophy that compromises normal CNS development and is caused by mutations in the gene for the enzyme ASPA (11, 12). ASPA currently is thought to function exclusively to hydrolyze NAA, a neuron-specific amino acid derivative, into L-aspartate and free acetate. However, ASPA is strongly expressed in other tissues, such as kidney, even though the only known substrate, NAA, is present predominantly in the nervous system (13). Despite the established connection between mutations in the gene for ASPA in CD and the lost capacity to deacetylate NAA, the specific connection between ASPA deficiency and the failure of proper CNS development is unclear (14). Furt...

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Acetyl transport mechanisms. Involvement of N-Acetyl aspartic acid in de novo fatty acid biosynthesis in the developing rat brain

Cited by 119 publications

References 22 publications

Absolute concentrations of metabolites in human brain tumors usingin vitro proton magnetic resonance spectroscopy

Absolute concentrations of metabolites in human brain tumors usingin vitro proton magnetic resonance spectroscopy

Proton Magnetic Resonance Spectroscopy in Dementia of Alzheimer Type

Defective N-acetylaspartate catabolism reduces brain acetate levels and myelin lipid synthesis in Canavan's disease

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