<i>N</i>‐acetylaspartic aciduria due to aspartoacylase deficiency — a new aetiology of childhood leukodystrophy

Hagenfeldt, Lars; Bollgren, I; Venizelos, Nikolaos

doi:10.1007/bf01800038

Cited by 115 publications

(72 citation statements)

References 18 publications

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“…Developmental increases in ASPA and NAA correlate with myelination (Burri et al 1991,D'Adamo et al 1973,Kirmani et al 2003 and several studies have shown incorporation of acetate from NAA into myelin lipids (Benuck & D'Adamo 1968,Burri et al 1991,Chakraborty et al 2001,D'Adamo & Yatsu 1966,Mehta & Namboodiri 1995. Total acetate levels and complete myelin lipid synthesis have recently been shown to be deficient in brains of CD knockout mice (Madhavarao et al 2005), providing strong support for the hypothesis that NAA in the CNS supplies acetyl groups for lipid synthesis during myelination (Hagenfeldt et al 1987,Kirmani et al 2002,Kirmani et al 2003,Madhavarao et al 2005,Mehta & Namboodiri 1995. Furthermore, ASPA is found in cells within both cytoplasm and nucleus (Hershfield et al 2006), though its role in the nucleus is yet to be delineated.…”

Section: Introductionmentioning

confidence: 90%

Mutational analysis of aspartoacylase: Implications for Canavan Disease

et al. 2007

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Mutations that result in undetectable activity of aspartoacylase, which catalyzes the deacetylation of N-acetyl-L-aspartate, correlate with Canavan Disease, a neurodegenerative disorder usually fatal during childhood. The underlying biochemical mechanisms of how these mutations ablate activity are poorly understood. Therefore, we developed and tested a three-dimensional homology model of aspartoacylase based on zinc dependent carboxypeptidase A. Mutations of the putative zinc-binding residues (H21G, E24D/G, and H116G), the general proton donor (E178A), and mutants designed to switch the order of the zinc-binding residues (H21E/E24H and E24H/H116E) yielded wild-type aspartoacylase protein levels and undetectable ASPA activity. Mutations that affect substrate carboxyl binding (R71N) and transition state stabilization (R63N) also yielded wild-type aspartoacylase protein levels and undetectable aspartoacylase activity. Alanine substitutions of Cys124 and Cys152, residues indicated by homology modeling to be in close proximity and in the proper orientation for disulfide bonding, yielded reduced ASPA protein and activity levels. Finally, expression of several previously tested (E24G, D68A, C152W, E214X, D249V, E285A, and A305E) and untested (H21P, A57T, I143T, P183H, M195R, K213E/G274R, G274R, and F295S) Canavan Disease mutations resulted in undetectable enzyme activity, and only E285A and P183H showed wild-type aspartoacylase protein levels. These results show that aspartoacylase is a member of the caboxypeptidase A family and offer novel explanations for most loss-of-function aspartoacylase mutations associated with Canavan Disease.

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Section: Introductionmentioning

confidence: 90%

Mutational analysis of aspartoacylase: Implications for Canavan Disease

et al. 2007

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“…Extracellular NAA has been shown to be preferentially taken up by astrocytes as opposed to neurons (Sager et al, 1999b) via the dicarboxylate transporter NaDC3, (Fujita et al, 2005;Ganapathy and Fujita, 2006;George et al, 2004;Huang et al, 2000), and NAA appears in urine at low micromolar concentrations, indicating that there is continuous efflux from the brain (Kelley and Stamas, 1992;Kvittingen et al, 1986;Miyake et al, 1982). Normal serum NAA levels are very low, and this may be due to glomerular filtration in the kidneys (Hagenfeldt et al, 1987). With regard to NAA clearance, it has been estimated that the human brain contains approximately 7 to 8 millimoles of NAA, and that normally about 1% is excreted in the urine per day (Miyake et al, 1982).…”

Section: Naa Transporters and Clearancementioning

confidence: 99%

“…However, other results have failed to show significant ASPA activity in O2A cells in culture (Madhavarao et al, 2002), and immunohistochemical studies have shown a complete lack of ASPA expression in astrocytes in the brain . Considering the facts that astrocytes form a significant portion of the blood-brain barrier, and that NAA is normally found in the urine (Hagenfeldt et al, 1987;Kvittingen et al, 1986), and that astrocytes express a sodium-dependent transporter for the uptake of extracellular NAA (Fujita et al, 2005), it seems likely that these glial cells take up extracellular NAA and excrete it to the circulation. In this regard it is interesting to note that we have observed NAAimmunoreactivity in a sub-population of brain endothelia ( Figure 5).…”

Section: Naa Transporters and Clearancementioning

confidence: 99%

“…Shortly thereafter, N-acetylaspartic aciduria was identified as being due to a deficiency of ASPA activity by Hagenfeldt and colleagues, who found reduced ASPA activity in skin fibroblasts from a child with severe leukodystrophy. They proposed that the observed dysmyelination in the CNS was due to a failure of NAA to serve as an acetate carrier of acetyl groups from mitochondria to cytoplasm for lipogenesis (Hagenfeldt et al, 1987). Matalon and colleagues were the first to connect Nacetylaspartic aciduria and ASPA deficiency specifically to Canavan disease by showing high NAA levels in urine, and a lack of ASPA activity in skin fibroblasts in 3 children with Canavan disease (Matalon et al, 1988).…”

Section: Naa and Canavan Diseasementioning

confidence: 99%

“…First was the prominence of the NAA proton signal in magnetic resonance spectroscopy (MRS), making NAA one of the most reliable markers for brain MRS studies (Barany et al, 1987;Fan et al, 1986;Luyten and den Hollander, 1986). The second was the connection to the rare but fatal hereditary genetic disorder known as Canavan disease (Bartalini et al, 1992;Divry and Mathieu, 1989;Hagenfeldt et al, 1987;Matalon et al, 1988).…”

Section: Introductionmentioning

confidence: 99%

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N-Acetylaspartate in the CNS: From neurodiagnostics to neurobiology

Moffett

Ross

Arun

et al. 2007

Progress in Neurobiology

1,213

1,126

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The brain is unique among organs in many respects, including its mechanisms of lipid synthesis and energy production. The nervous system-specific metabolite N-acetylaspartate (NAA), which is synthesized from aspartate and acetyl-coenzyme A in neurons, appears to be a key link in these distinct biochemical features of CNS metabolism. During early postnatal CNS development, the expression of lipogenic enzymes in oligodendrocytes, including the NAA-degrading enzyme aspartoacylase (ASPA), is increased along with increased NAA production in neurons. NAA is transported from neurons to the cytoplasm of oligodendrocytes, where ASPA cleaves the acetate moiety for use in fatty acid and steroid synthesis. The fatty acids and steroids produced then go on to be used as building blocks for myelin lipid synthesis. Mutations in the gene for ASPA result in the fatal leukodystrophy Canavan disease, for which there is currently no effective treatment. Once postnatal myelination is completed, NAA may continue to be involved in myelin lipid turnover in adults, but it also appears to adopt other roles, including a bioenergetic role in neuronal mitochondria. NAA and ATP metabolism appear to be linked indirectly, whereby acetylation of aspartate may facilitate its removal from neuronal mitochondria, thus favoring conversion of glutamate to alpha ketoglutarate which can enter the tricarboxylic acid cycle for energy production. In its role as a mechanism for enhancing mitochondrial energy production from glutamate, NAA is in a key position to act as a magnetic resonance spectroscopy marker for neuronal health, viability and number. Evidence suggests that NAA is a direct precursor for the enzymatic synthesis of the neuron specific dipeptide N-acetylaspartylglutamate, the most concentrated neuropeptide in the human brain. Other proposed roles for NAA include neuronal osmoregulation and axon-glial signaling. We propose that NAA may also be involved in brain nitrogen balance. Further research will be required to more fully understand the biochemical functions served by NAA in CNS development and activity, and additional functions are likely to be discovered.

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Serum <emph type="ital">N</emph> -acetylaspartate Level in Amyotrophic Lateral Sclerosis

Simone

Ruggieri²,

Tortelli³

et al. 2011

Arch Neurol

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Background: N-acetylaspartate (NAA) level is a biomarker of functional integrity and vitality in neurons. In vivo multisection proton ( 1 H)-magnetic resonance spectroscopy studies indicate that NAA level decreases in specific cortical brain areas of patients with amyotrophic lateral sclerosis (ALS).Objective: To study NAA level in serum samples as a possible biomarker of ALS.Design: Serum NAA assay by liquid chromatographymass spectrometry in a case-control series.

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N‐acetylaspartic aciduria due to aspartoacylase deficiency — a new aetiology of childhood leukodystrophy

Cited by 115 publications

References 18 publications

Mutational analysis of aspartoacylase: Implications for Canavan Disease

Mutational analysis of aspartoacylase: Implications for Canavan Disease

N-Acetylaspartate in the CNS: From neurodiagnostics to neurobiology

Serum <emph type="ital">N</emph> -acetylaspartate Level in Amyotrophic Lateral Sclerosis

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