Knock-out mouse for Canavan disease: a model for gene transfer to the central nervous system

Matalon, Reuben; Rády, Peter L.; Platt, Kenneth A.; Skinner, Henry B.; Quast, Michael J.; Campbell, Gerald A.; Matalon, Kimberlee Michals; Ceci, Jeffrey D.; Tyring, Stephen K.; Nehls, Michael; Surendran, Sankar; Wei, Jingna; Ezell, Edward L.; Szucs, Sylvia

doi:10.1002/(sici)1521-2254(200005/06)2:3<165::aid-jgm107>3.0.co;2-r

Cited by 124 publications

(80 citation statements)

References 48 publications

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“…In addition to causing accumulation of NAA in brain and other tissues, loss of ASPA activity leads to spongy degeneration of white matter associated with progressive loss of myelin [3,4]. Animal models with inactivated ASPA have proved useful in the study of this condition, as with the knockout mouse that was shown to have morphologically abnormal myelin [5]. Similarly, the tremor rat, employed in this study, which possesses a natural ASPA mutation, was shown to have hypomyelination, vacuolation along with spongy degeneration of white matter [26], and in addition loss of oligodendrocytes [27].…”

Section: Discussionmentioning

confidence: 99%

“…This autosomal recessive childhood disorder is characterized by CNS swelling and spongy degeneration of white matter, along with accumulation of N-acetylaspartate (NAA) in brain and urine [3,4]. White matter pathology in rodent models, such as the ASPA-null knockout mouse, was shown to involve myelin vacuolization as a feature of dysmyelination and/or demyelination [5]. Those findings were consistent with previous reports suggesting a vital role for ASPA and its NAA substrate in myelination, including the finding of incorporation of the acetyl component of NAA into brain-and myelin lipids [6][7][8].…”

Section: Introductionmentioning

confidence: 99%

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Myelin Lipid Abnormalities in the Aspartoacylase-Deficient Tremor Rat

Wang

Leone

et al. 2008

Neurochem Res

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The high concentration of N-acetylaspartate (NAA) in neurons of the central nervous system and its growing clinical use as an indicator of neuronal viability has intensified interest in the biological function of this amino acid derivative. The biomedical relevance of such inquiries is highlighted by the myelin-associated pathology of Canavan disease, an inherited childhood disorder resulting from mutation of aspartoacylase (ASPA), the NAA-hydrolyzing enzyme. This enzyme is known to be localized in oligodendrocytes with bimodal distribution in cytosol and the myelin sheath, and to produce acetyl groups utilized in myelin lipid synthesis. Loss of this acetyl source in Canavan disease and rodent models such as the tremor rat are thought to account for the observed myelin deficit. This study was undertaken to further define and quantify the specific lipid abnormalities that occur as a result of ASPA deficit in the tremor rat. Employing mass spectrometry together with high performance thin-layer chromatography, we found that myelin from 28-day-old animals showed major reduction in cerebrosides (CB) and sulfatides (Sulf) with unsubstituted fatty acids, and equal if not greater changes in myelin from 7-month-old tremors. Cerebrosides with 2-hydroxyfatty acids showed little if any change at either age; Sulf with 2-hydroxyfatty acids showed no significant change at 28 days, but surprisingly a major increase at 7 months. Two species of phosphatidylcholine, 32:0 and 34:1, also showed significant increase, but only at 28 days. One form of phosphatidylethanolamine, PE36:1, was reduced a modest amount at both ages, whereas the plasmalogen form did not change. The dysmyelination that results from inactivation of ASPA is thus characterized by selective decreases as well as some increases in specific lipids.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Myelin Lipid Abnormalities in the Aspartoacylase-Deficient Tremor Rat

Wang

Leone

et al. 2008

Neurochem Res

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“…NAA is released from neurons to the cerebrospinal fluid and then transported to oligodendrocytes (6,7). Although the exact role of NAA in the brain remains a matter of investigations (1,2,(8)(9)(10)(11), it is believed that proper metabolism of this compound in the brain is important for correct development and maintenance of the white matter (12,13).…”

mentioning

confidence: 99%

“…Measurement of elevated NAA levels in urine is used to confirm the diagnosis of CD (24). A mouse knockout model deficient in ASPA activity (13) and a rat model with a natural deletion of the aspartoacylase gene (26) have been recently developed and serve as important tools in understanding biochemical pathologies related to CD (10,(27)(28)(29).…”

mentioning

confidence: 99%

Structure of aspartoacylase, the brain enzyme impaired in Canavan disease

Bitto

Bingman

Wesenberg

et al. 2007

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

120

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Aspartoacylase catalyzes hydrolysis of N-acetyl-L-aspartate to aspartate and acetate in the vertebrate brain. Deficiency in this activity leads to spongiform degeneration of the white matter of the brain and is the established cause of Canavan disease, a fatal progressive leukodystrophy affecting young children. We present crystal structures of recombinant human and rat aspartoacylase refined to 2.8-and 1.8-Å resolution, respectively. 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. The catalytic site of aspartoacylase shows close structural similarity to those of carboxypeptidases despite only 10 -13% sequence identity between these proteins. About 100 C-terminal residues of aspartoacylase form a globular domain with a two-stranded ␤-sheet linker that wraps around the N-terminal domain. The long channel leading to the active site is formed by the interface of the N-and C-terminal domains. The C-terminal domain is positioned in a way that prevents productive binding of polypetides in the active site. The structures revealed that residues 158 -164 may undergo a conformational change that results in opening and partial closing of the channel entrance. We hypothesize that the catalytic mechanism of aspartoacylase is closely analogous to that of carboxypeptidases. We identify residues involved in zinc coordination, and propose which residues may be involved in substrate binding and catalysis. The structures also provide a structural framework necessary for understanding the deleterious effects of many missense mutations of human aspartoacylase.N-acetyl-L-aspartate ͉ x-ray structure ͉ zinc-dependent hydrolase

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“…The disease has been found to result from mutations of the glial fibrillary acidic protein gene [33], but attempts to create an animal model using knockout or knockin strategies have failed to produce any myelin changes [33]. The final disease to be considered is Canavan disease, which results from mutations in the aspartoacylase gene, leading to profound vacuolation of white matter as is found in a knockout of the gene [34,35] and in a point mutation in the rat model [36]. However, there is little or no evidence that the white matter change leads to significant demyelination, hence promoting remyelination would not seem to be a useful therapeutic strategy.…”

Section: Diseases To Be Targeted By Exogenous Cell Therapymentioning

confidence: 99%

The Myelin Mutants as Models to Study Myelin Repair in the Leukodystrophies

2011

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The leukodystrophies are rare and serious genetic disorders of the central nervous system that primarily affect children who frequently die early in life or have significantly delayed motor and mental milestones that result in long-term disability. Although with some of these disorders, early intervention with bone marrow or cord blood transplantation has been proven useful, it has not yet been determined that such therapies promote myelin repair of the central nervous system. Research on experimental therapies aimed at myelin repair is aided by the ability to test cell replacement strategies in genetic models in which the mutations and neuropathology match the human disorder. Thus, models exist of Pelizaeus-Merzbacher disease and the lysosomal storage disorder, Krabbe disease, which reflect the clinical and pathological course of the human disorders. Collectively, animals with mutations in myelin genes are called the myelin mutants, and they include rodent models such as the shiverer mouse that have been extensively used to study myelination by exogenous cell transplantation. These studies have encompassed many permutations of the age of the recipient, type of transplanted cell, site of engraftment, and so forth, and they offer hope that the scaling up of myelin produced by transplanted cells will have clinical significance in treating patients. Here we review these models and discuss their relative importance and use in such translational approaches. We discuss how grafts are identified and functional outcomes are measured. Finally, we briefly discuss the cells that have been successfully transplanted, which may be used in future clinical trials.

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Knock-out mouse for Canavan disease: a model for gene transfer to the central nervous system

Cited by 124 publications

References 48 publications

Myelin Lipid Abnormalities in the Aspartoacylase-Deficient Tremor Rat

Myelin Lipid Abnormalities in the Aspartoacylase-Deficient Tremor Rat

Structure of aspartoacylase, the brain enzyme impaired in Canavan disease

The Myelin Mutants as Models to Study Myelin Repair in the Leukodystrophies

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