Aspartoacylase is a regulated nuclear‐cytoplasmic enzyme

@article{Hershfield2006AspartoacylaseIA,
  title={Aspartoacylase is a regulated nuclear‐cytoplasmic enzyme},
  author={Jeremy R. Hershfield and C. N. Madhavarao and J. Moffett and J. Benjamins and J. Garbern and A. Namboodiri},
  journal={The FASEB Journal},
  year={2006},
  volume={20},
  pages={E1482 - E1494}
}
Mutations in the gene for aspartoacylase (ASPA), which catalyzes deacetylation of N‐acetyl‐L‐aspartate in the central nervous system (CNS), result in Canavan Disease, a fatal dysmyelinating disease. Consistent with its role in supplying acetate for myelin lipid synthesis, ASPA is thought to be cytoplasmic. Here we describe the occurrence of ASPA within nuclei of rat brain and kidney, and in cultured rodent oligodendrocytes. Immunohistochemistry showed cytoplasmic and nuclear ASPA staining, the… Expand
Extensive aspartoacylase expression in the rat central nervous system
Aspartoacylase (ASPA) catalyzes deacetylation of N‐acetylaspartate (NAA) to generate acetate and aspartate. Mutations in the gene for ASPA lead to reduced acetate availability in the CNS duringExpand
Structure of aspartoacylase, the brain enzyme impaired in Canavan disease
TLDR
The structures revealed that the N-terminal domain of aspartoacylase adopts a protein fold similar to that of zinc-dependent hydrolases related to carboxypeptidases A, and suggested that residues 158–164 may undergo a conformational change that results in opening and partial closing of the channel entrance. Expand
Aspartoacylase-LacZ Knockin Mice: An Engineered Model of Canavan Disease
TLDR
The aspalacZ mouse is an accurate model of CD and an important tool to identify novel aspects of its complex pathology. Expand
Nuclear‐cytoplasmic localization of acetyl coenzyme a synthetase‐1 in the rat brain
TLDR
The strong AceCS1 expression observed in the nuclei of CNS cells during brain development and after injury is consistent with a role in nuclear histone acetylation and therefore the regulation of chromatin structure and gene expression and suggests an additional role in CNS lipid synthesis and myelination. Expand
Expression of aspartoacylase (ASPA) and Canavan disease.
TLDR
Researchers found high levels of human ASPA gene expression not only in brain and kidney, but also in lung and liver using the HEK293 cell line, which provides the authentic human machinery for posttranslational modifications. Expand
Nur7 Is a Nonsense Mutation in the Mouse Aspartoacylase Gene That Causes Spongy Degeneration of the CNS
TLDR
It is found that myelin degeneration leads to significant axonal loss in the cerebellum of older Aspanur7 mutants, which suggests that axonal pathology caused by CNS myelin defects may underlie the neurological disabilities that CD patients develop at late stages of the disease. Expand
Mutational analysis of aspartoacylase: Implications for Canavan Disease
TLDR
A three-dimensional homology model of aspartoacylase based on zinc dependent carboxypeptidase A shows that it is a member of the caboxypeptIDase A family and offers novel explanations for most loss-of-function asparticlase mutations associated with Canavan Disease. Expand
N-Acetylaspartate in the CNS: From neurodiagnostics to neurobiology
TLDR
Evidence suggests that NAA is a direct precursor for the enzymatic synthesis of the neuron specific dipeptides N-acetylaspartylglutamate, the most concentrated neuropeptide in the human brain, and it is proposed that N AA may also be involved in brain nitrogen balance. Expand
N-acetylaspartate synthesis in the brain: Mitochondria vs. microsomes
TLDR
This work reinvestigated the issue of microsomal localization of the NAA biosynthetic enzyme in rat brain homogenates using a similar fractionation procedure used by Lu et al. but without the loss of enzyme activity that they have encountered and found similar results in the case of the enzyme from bovine brain. Expand
Increasing N-acetylaspartate in the Brain during Postnatal Myelination Does Not Cause the CNS Pathologies of Canavan Disease
TLDR
Results show that ASPA expression prevents the pathologies associated with excessive NAA concentrations in the brain during postnatal myelination and hypothesize that the pathogenesis of Canavan disease involves not only disrupted NAA metabolism, but also excessive N AA related signaling processes in oligodendrocytes. Expand
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The predominant immunoreactivity in oligodendrocytes is consistent with the proposed role of ASPA in myelination, supporting the case for acetate supplementation as an immediate and inexpensive therapy for infants diagnosed with CD. Expand
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TLDR
The clinically relevant E285A mutant reveals an altered enzyme with poor stability and barely detectable activity, while a more conservative E285D substitution leads to only fivefold lower activity than native aspartoacylase. Expand
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Biochemical and immunocytochemical studies revealed that aspartoacylase is localized to white matter, whereas the N‐acetylaspartic acid concentration is threefold higher in gray matter than in white matter. Expand
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TLDR
A highly specific polyclonal antibody is generated and characterized which recognizes a 37 kDa monomer and a dimer in normal but not in aspartoacylase-deficient rat tissue, revealing immunoreactivity is restricted to oligodendrocyte somata in both white and gray matter. Expand
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TLDR
The 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. Expand
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TLDR
The results of this study show for the first time that aspartoacylase activity is expressed only in oligodendrocytes, and the meaning of this observation in understanding the function of the NAA metabolic cycle is discussed. Expand
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TLDR
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TLDR
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TLDR
The developmental expression pattern of aspartoacylase gene in the postnatal brain closely parallels myelination in the CNS, indicating that the role of N-acetylaspartate in myelin synthesis is restricted to the CNS and providing additional support for the acetate deficiency hypothesis of Canavan disease. Expand
Aspartoacylase is restricted primarily to myelin synthesizing cells in the CNS: therapeutic implications for Canavan disease.
TLDR
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. Expand
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