Expression of aspartoacylase (ASPA) and Canavan disease

Sommer, Anke; Sass, Jörn Oliver

doi:10.1016/j.gene.2012.06.036

Cited by 15 publications

(9 citation statements)

References 32 publications

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“…The activity measured for the WT (6,180 ± 1,223 nmol Asp/hr/mg) and for the variant p.Glu285Ala (about 2% of WT) match the activities described in the literature [Kaul et al, 1994;Moore et al, 2003;Sommer and Sass, 2012], validating our method. Different phenotypic presentations have been described for CD.…”

Section: Discussionsupporting

confidence: 85%

“…ASPA (EC3.5.1.15) is a dimeric metalloenzyme composed by 37 kDa monomers (313 amino acid residues). It is mainly present in brain white matter (mainly oligodendrocytes) and kidney [Baslow et al, 1999;Sommer and Sass, 2012]. The crystal structure of ASPA has been resolved (Bitto et al, 2007;Le Coq et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

“…It was shown that due to rare codon usage, eukaryotic expression systems need to be used to properly study enzyme variants [Wang and Viola, 2014]. The vast majority of ASPA mutations that have been overexpressed in COS or human embryonic kidney (HEK)293 cells present very low enzyme activity (lower than 5% of wild-type (WT)) [Janson et al, 2006;Sommer and Sass, 2012;Surendran et al, 2003a].…”

Section: Introductionmentioning

confidence: 99%

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Clinically Distinct Phenotypes of Canavan Disease Correlate with Residual Aspartoacylase Enzyme Activity

et al. 2017

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We describe 14 patients with 12 novel missense mutations in ASPA, the gene causing Canavan disease (CD). We developed a method to study the effect of these 12 variants on the function of aspartoacylase—the hydrolysis of N‐acetyl‐l‐aspartic acid (NAA) to aspartate and acetate. The wild‐type ASPA open reading frame (ORF) and the ORFs containing each of the variants were transfected into HEK293 cells. Enzyme activity was determined by incubating cell lysates with NAA and measuring the released aspartic acid by LC–MS/MS. Clinical data were obtained for 11 patients by means of questionnaires. Four patients presented with a non‐typical clinical picture or with the milder form of CD, whereas seven presented with severe CD. The mutations found in the mild patients corresponded to the variants with the highest residual enzyme activities, suggesting that this assay can help evaluate unknown variants found in patients with atypical presentation. We have detected a correlation between clinical presentation, enzyme activity, and genotype for CD.

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Section: Discussionsupporting

confidence: 85%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Clinically Distinct Phenotypes of Canavan Disease Correlate with Residual Aspartoacylase Enzyme Activity

et al. 2017

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“…Reduced BUN and BUN/creatinine ratios in the range observed in the M-NAA treated group are not indicative of kidney or liver dysfunction, and similar results on BUN have been reported in a previous study of male rats fed 500 mg/kg NAA per day for 90 days (Karaman et al, 2011). The kidney has higher Aspa expression and activity levels than the brain (Hershfield et al, 2006; Sommer and Sass, 2012), and it is possible that NAA catabolism in the kidneys facilitates or enhances urea excretion by an unknown mechanism. NAA has been proposed to facilitate nitrogen removal from the brain (Moffett et al, 2007), but potential roles for NAA in nitrogen balance have not been investigated in any tissue.…”

Section: Discussionmentioning

confidence: 99%

Increasing N-acetylaspartate in the Brain during Postnatal Myelination Does Not Cause the CNS Pathologies of Canavan Disease

Appu

Moffett

Arun

et al. 2017

Front. Mol. Neurosci.

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Canavan disease is caused by mutations in the gene encoding aspartoacylase (ASPA), a deacetylase that catabolizes N-acetylaspartate (NAA). The precise involvement of elevated NAA in the pathogenesis of Canavan disease is an ongoing debate. In the present study, we tested the effects of elevated NAA in the brain during postnatal development. Mice were administered high doses of the hydrophobic methyl ester of NAA (M-NAA) twice daily starting on day 7 after birth. This treatment increased NAA levels in the brain to those observed in the brains of Nur7 mice, an established model of Canavan disease. We evaluated various serological parameters, oxidative stress, inflammatory and neurodegeneration markers and the results showed that there were no pathological alterations in any measure with increased brain NAA levels. We examined oxidative stress markers, malondialdehyde content (indicator of lipid peroxidation), expression of NADPH oxidase and nuclear translocation of the stress-responsive transcription factor nuclear factor (erythroid-derived 2)-like 2 (NRF-2) in brain. We also examined additional pathological markers by immunohistochemistry and the expression of activated caspase-3 and interleukin-6 by Western blot. None of the markers were increased in the brains of M-NAA treated mice, and no vacuoles were observed in any brain region. These results show that ASPA expression prevents the pathologies associated with excessive NAA concentrations in the brain during postnatal myelination. We hypothesize that the pathogenesis of Canavan disease involves not only disrupted NAA metabolism, but also excessive NAA related signaling processes in oligodendrocytes that have not been fully determined and we discuss some of the potential mechanisms.

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“…Currently, >54 mutations are associated with Canavan's disease (Hershfield et al 2007) with new mutations being identified on a regular basis. Several mutations have been identified to result in a loss of aspartoacylase activity as well as lack of expression (Sommer and Sass 2012) though all mutations have not been completely characterized; hence, DNA analysis limits prenatal diagnosis to carrier couples in populations with known mutations. The previous method of measuring AspA activity in the chorionic villi or amniocytes from fetuses was deemed unreliable (Matalon and Michals-Matalon 1999a).…”

mentioning

confidence: 99%

Expression of aspartoacylase (ASPA) and Canavan disease

Cited by 15 publications

References 32 publications

Clinically Distinct Phenotypes of Canavan Disease Correlate with Residual Aspartoacylase Enzyme Activity

Clinically Distinct Phenotypes of Canavan Disease Correlate with Residual Aspartoacylase Enzyme Activity

Increasing N-acetylaspartate in the Brain during Postnatal Myelination Does Not Cause the CNS Pathologies of Canavan Disease

Making the White Matter Matters: Progress in Understanding Canavan’s Disease and Therapeutic Interventions Through Eight Decades

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