Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Canavan disease (CD), a rare recessive autosomal genetic disorder, is characterized by early onset and a progressive spongy degeneration of the brain involving loss of the axon's myelin sheath. After a relatively normal birth, homozygous individuals generally develop clinical symptoms within months, and usually die within several years of the onset of the disease. A biochemical defect associated with this disease results in reduced activity of the enzyme N-acetyl-L-aspartate amidohydrolase (aspartoacylase) and affected individuals have less ability to hydrolyze N-acetyl-L-asparate (NAA) in brain and other tissues. As a result of aspartoacylase deficiency, NAA builds up in extracellular fluids (ECF) and is excreted in urine. From an analysis of the NAA biochemical cycle in various tissues of many vertebrate species, evidence is presented that there may be two distinct NAA circulation patterns related to aspartoacylase activity. These include near-field circulations in the brain and the eye, and a far-field systemic circulation involving the liver and kidney, the purpose of which in each case is apparently to regenerate aspartate (Asp) in order for it to be recycled into NAA as part of the still unknown function of the NAA cycle. Based on the authors' analysis, they have also identified several metabolic outcomes of the genetic biochemical aspartoacylase lesion. First, there is a daily induced Asp deficit in the central nervous system (CNS) that is at least six times the static level of available free Asp. Second, there is up to a 50-fold drop in the intercompartmental NAA gradient, and third, the ability of the brain to perform its normal intercompartmental cycling of NAA to Asp is terminated, and as a result, the only remaining long-term source of Asp for NAA synthesis is via nutritional supplementation of Asp or its metabolic precursors. Finally, the authors identify a potential maternal-fetal interaction that may be responsible for observed normal fetal development in utero, and that provides a rationale for, and suggests how, CD might respond to far-field nutritional, transplantation, or genetic engineering techniques to alter the course of the disease.
J Mol Neurosci 1997 Oct
PMID:Canavan disease. Analysis of the nature of the metabolic lesions responsible for development of the observed clinical symptoms. 940 92

Zn-dependent carboxypeptidases (ZnCP) cleave off the C-terminal amino acid residues from proteins and peptides. Here we describe a superfamily that unites classical ZnCP with other enzymes, most of which are known (or likely) to participate in metal-dependent peptide bond cleavage, but not necessarily in polypeptide substrates. It is demonstrated that aspartoacylase (ASP gene) and succinylglutamate desuccinylase (ASTE gene) are members of the ZnCP family. The Zn-binding site along with the structural core of the protein is shown to be conserved between ZnCP and another large family of hydrolases that includes mostly aminopeptidases (ZnAP). Both families (ZnCP and ZnAP) include not only proteases but also enzymes that perform N-deacylation, and enzymes that catalyze N-desuccinylation of amino acids. This is a result of functional convergence that apparently occurred after the divergence of the two families.
J Mol Biol 1999 Sep 10
PMID:The Zn-peptidase superfamily: functional convergence after evolutionary divergence. 1049 53

N-acetyl-L-aspartate (NAA) is an important osmolyte in the vertebrate brain and eye, and its cyclical metabolism is accomplished in two separate compartments. In the brain, NAA is synthesized primarily in neurons, and after its regulated release, NAA is hydrolyzed by aspartoacylase, which is present in a glial-associated compartment. However, the precise nature of this hydrolytic compartment has remained obscure. It has been proposed that one role of aspartoacylase in the central nervous system (CNS) is as part of a molecular water pump (MWP) that uses the NAA intercompartmental cycle to remove nerve cell metabolic water against a water gradient and that oligodendrocytes comprise the second compartment in this metabolic sequence. The absence of aspartoacylase activity in Canavan disease (CD), a rare early onset genetic spongiform leukodystrophy, is associated with CNS edema, intramyelinic swelling and a progressive loss of oligdendrocytes. In order to evaluate the MWP hypothesis and its possible relationship to the etiology of CD further, both oligodendrocytes and astrocytes obtained from neonatal rat brain were grown in culture and tested for the presence of aspartoacylase activity. The results of this study show for the first time that aspartoacylase activity is expressed only in oligodendrocytes. The meaning of this observation in understanding the function of the NAA metabolic cycle is discussed.
J Mol Neurosci
PMID:Expression of aspartoacylase activity in cultured rat macroglial cells is limited to oligodendrocytes. 1069 Dec 91

Canavan disease is caused by mutations in aspartoacylase, the enzyme that degrades N-acetylaspartate (NAA) into acetate and aspartate. Murine aspartoacylase (mASPA) was cloned using sequence information from mouse expressed sequence tags homologous to the human cDNA. The open reading frame was cloned into a thioredoxin fusion vector, overexpressed in bacteria, and the protein was purified using affinity chromatography to near homogeneity. Recombinant human ASPA (hASPA) was prepared by a similar method. Both recombinant enzymes were highly specific to NAA, with about 10% of the NAA activity toward N-acetylasparagine. More interestingly, the product of N-acetylasparagine was aspartate but not asparagine, indicating that ASPA catalyzed deacetylation as well as hydrolysis of the beta acid amide. Our success in preparing the recombinant ASPA in high purity should permit multiple lines of investigations to understand the pathogenic mechanisms of Canavan disease and the functional roles of NAA.
Brain Res Mol Brain Res 2000 May 05
PMID:Murine aspartoacylase: cloning, expression and comparison with the human enzyme. 1083 25

Canavan disease (CD) is a globally distributed early-onset leukodystrophy. It is genetic in nature, and results from an autosomally inherited recessive trait that is characterized by loss of the axon's myelin sheath while leaving the axons intact, and spongiform degeneration especially in white matter. There is also a buildup of N-acetyl-L-aspartate (NAA) in brain, as well as NAA acidemia and NAA aciduria. The cause of the altered NAA metabolism has been traced to several mutations in the gene for the production of aspartoacylase, located on chromosome 17, which is the primary enzyme involved in the catabolic metabolism of NAA. In this review, an attempt is made to correlate the change in NAA metabolism that results from the genetic defects in CD with the processes involved in the development of the CD syndrome. In addition, present efforts to counter the results of the genetic defects in this disease are also considered.
J Mol Neurosci 2000 Oct
PMID:Canavan's spongiform leukodystrophy: a clinical anatomy of a genetic metabolic CNS disease. 1122 Jul 86

The neurogenetic prototypic disease on which we chose to test our gene therapy strategy is Canavan disease (CD). CD is an autosomal recessive leukodystrophy associated with spongiform degeneration of the brain. At present the disease is uniformly fatal in affected probands. CD is characterized by mutations in the aspartoacylase (ASPA) gene, resulting in loss of enzyme activity. In this review, recent evidence is summarized on the etiology and possible treatments for CD. In particular, we discuss two gene delivery systems representing recent advances in both viral and liposome technology: a novel cationic liposome-polymer-DNA (LPD) complex, DCChol/DOPE-protamine, as well as recombinant adeno-associated virus (AAV) vectors.
Curr Opin Mol Ther 1999 Aug
PMID:Global CNS gene transfer for a childhood neurogenetic enzyme deficiency: Canavan disease. 1171 64

Canavan disease is a devastating neurodegenerative childhood disease caused by mutations in aspartoacylase, an enzyme that deacetylates N-acetylaspartate to generate free acetate in the brain. Localization of aspartoacylase in different cell types in the rat brain was examined in an attempt to understand the pathogenesis of Canavan disease. In situ hybridization histochemistry with a riboprobe based on murine aspartoacylase cDNA was used in this study. The hybridization signal was detectable primarily in the myelin-synthesizing cells, namely oligodendroglia. These findings provide strong additional support for insufficient myelin synthesis as the pathogenic basis of Canavan disease and make a compelling case for acetate supplementation as a simple and noninvasive therapy for this fatal disease with no treatment.
Brain Res Mol Brain Res 2002 Nov 15
PMID:Aspartoacylase is restricted primarily to myelin synthesizing cells in the CNS: therapeutic implications for Canavan disease. 1248 23

A recent study showing incorporation of acetyl groups from neuronal N-acetylaspartate into myelin lipids suggested the presence of fatty acid synthesizing enzymes in myelin that utilize the acetyl groups liberated by myelin-associated aspartoacylase [J. Neurochem. 78 (2001) 736]. We report here detection of the fatty acid synthase (FAS) complex and acetyl-CoA carboxylase (ACC) in purified myelin. The activity of myelin FAS was approximately half that of cytosolic FAS and, unlike the latter, required detergent for activation. Intrinsic association of FAS with myelin was indicated by failure to remove the activity with NaCl or Na-taurocholate. Myelin-associated ACC was approximately 10% of cytosolic ACC in myelin isolated by gradient centrifugation, and this was reduced by half following osmotic shock; this suggested bimodal distribution of myelin ACC, some being loosely associated within inter-lamellar cytoplasmic spaces and the remainder more firmly associated in a manner that resists NaCl/Na-taurocholate treatments. These results, in combination with earlier findings, provide a possible mechanism for the observed incorporation of neuronal NAA acetyl groups into myelin lipids.
Brain Res Mol Brain Res 2003 Apr 10
PMID:Fatty acid synthesizing enzymes intrinsic to myelin. 1267 Jul 1

Canavan disease (CD) is an autosomal recessive leukodystrophy caused by deficiency of aspartoacylase (ASPA). Deficiency of ASPA leads to elevation of N-acetyl-L-aspartic acid (NAA) in the brain and urine. To explore the feasibility of gene transfer to replace ASPA in CD, we generated a knockout mouse and constructed an AAV vector that encodes human ASPA cDNA (hASPA) followed by green fluorescent protein (GFP) after an intraribosomal entry site. We injected CD mice with rAAV-hASPA-GFP in the striatum and thalamus or injected rAAV-GFP identically into control animals. Three to five months after the injection, we determined the presence of ASPA in the CD mouse brain by ASPA activity assay, GFP expression, and Western blot analysis. While rAAV-GFP-injected animals displayed undetectable levels of ASPA, all detection methods revealed significant ASPA levels in rAAV-hASPA-GFP-injected CD mice. We evaluated the functional effects of rAAV-hASPA-GFP-mediated ASPA expression by standard histological methods, magnetic resonance spectroscopy (MRS) for in vivo NAA levels, and magnetic resonance imaging of CD mice. rAAV-hASPA-injected animals displayed a remarkable lack of spongiform degeneration in the thalamus. However, pathology in sites unrelated to the injected areas showed no improvement in histopathology. The improvement in thalamic neuropathology was also detectable via in vivo MRI. MRS revealed that in vivo NAA levels were also reduced. These data indicate that rAAV-mediated ASPA delivery may be an interesting avenue for the treatment of CD.
Mol Ther 2003 May
PMID:Adeno-associated virus-mediated aspartoacylase gene transfer to the brain of knockout mouse for canavan disease. 1271

Canavan disease (CD) is an inherited leukodystrophy, caused by aspartoacylase (ASPA) deficiency, and accumulation of N-acetylaspartic acid (NAA) in the brain. The gene for ASPA has been cloned and more than 40 mutations have been described, with two founder mutations among Ashkenazi Jewish patients. Screening of Ashkenazi Jews for these two common mutations revealed a high carrier frequency, approximately 1/40, so that programs for carrier testing are currently in practice. The enzyme deficiency in CD interferes with the normal hydrolysis of NAA, which results in disruption of myelin and spongy degeneration of the white matter of the brain. The clinical features of the disease are macrocephaly, head lag, progressive severe mental retardation, and hypotonia in early life, which later changes to spasticity. A knockout mouse for CD has been generated, and used to study the pathophysiological basis for CD. Findings from the knockout mouse indicate that this monogenic trait leads to a series of genomic interaction in the brain. Changes include low levels of glutamate and GABA. Microarray expression analysis showed low level of expression of GABA-A receptor (GABRA6) and glutamate transporter (EAAT4). The gene Spi2, a gene involved in apoptosis and cell death, showed high level of expression. Such complexity of gene interaction results in the phenotype, the proteome, with spongy degeneration of the brain and neurological impairment of the mouse, similar to the human counterpart. Aspartoacylase gene transfer trial in the mouse brain using adenoassociated virus (AAV) as a vector are encouraging showing improved myelination and decrease in spongy degeneration in the area of the injection and also beyond that site.
Mol Genet Metab
PMID:Canavan disease: a monogenic trait with complex genomic interaction. 1456 59


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