Cellular and molecular mechanisms of aspartoacylase and its role in Canavan disease
Abstract Canavan disease is an autosomal recessive and lethal neurological disorder, characterized by the spongy degeneration of the white matter in the brain. The disease is caused by a deficiency of the cytosolic aspartoacylase (ASPA) enzyme, which catalyzes the hydrolysis of N-acetyl-aspartate (N...
| Main Authors: | , |
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| Format: | Article |
| Language: | English |
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BMC
2024-04-01
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| Series: | Cell & Bioscience |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13578-024-01224-6 |
| _version_ | 1827291351636508672 |
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| author | Martin Grønbæk-Thygesen Rasmus Hartmann-Petersen |
| author_facet | Martin Grønbæk-Thygesen Rasmus Hartmann-Petersen |
| author_sort | Martin Grønbæk-Thygesen |
| collection | DOAJ |
| description | Abstract Canavan disease is an autosomal recessive and lethal neurological disorder, characterized by the spongy degeneration of the white matter in the brain. The disease is caused by a deficiency of the cytosolic aspartoacylase (ASPA) enzyme, which catalyzes the hydrolysis of N-acetyl-aspartate (NAA), an abundant brain metabolite, into aspartate and acetate. On the physiological level, the mechanism of pathogenicity remains somewhat obscure, with multiple, not mutually exclusive, suggested hypotheses. At the molecular level, recent studies have shown that most disease linked ASPA gene variants lead to a structural destabilization and subsequent proteasomal degradation of the ASPA protein variants, and accordingly Canavan disease should in general be considered a protein misfolding disorder. Here, we comprehensively summarize the molecular and cell biology of ASPA, with a particular focus on disease-linked gene variants and the pathophysiology of Canavan disease. We highlight the importance of high-throughput technologies and computational prediction tools for making genotype–phenotype predictions as we await the results of ongoing trials with gene therapy for Canavan disease. |
| first_indexed | 2024-04-24T12:35:31Z |
| format | Article |
| id | doaj.art-d16159e3d96d4829b453b859feaeacf5 |
| institution | Directory Open Access Journal |
| issn | 2045-3701 |
| language | English |
| last_indexed | 2024-04-24T12:35:31Z |
| publishDate | 2024-04-01 |
| publisher | BMC |
| record_format | Article |
| series | Cell & Bioscience |
| spelling | doaj.art-d16159e3d96d4829b453b859feaeacf52024-04-07T11:32:12ZengBMCCell & Bioscience2045-37012024-04-0114113310.1186/s13578-024-01224-6Cellular and molecular mechanisms of aspartoacylase and its role in Canavan diseaseMartin Grønbæk-Thygesen0Rasmus Hartmann-Petersen1The Linderstrøm-Lang Centre for Protein Science, Department of Biology, University of CopenhagenThe Linderstrøm-Lang Centre for Protein Science, Department of Biology, University of CopenhagenAbstract Canavan disease is an autosomal recessive and lethal neurological disorder, characterized by the spongy degeneration of the white matter in the brain. The disease is caused by a deficiency of the cytosolic aspartoacylase (ASPA) enzyme, which catalyzes the hydrolysis of N-acetyl-aspartate (NAA), an abundant brain metabolite, into aspartate and acetate. On the physiological level, the mechanism of pathogenicity remains somewhat obscure, with multiple, not mutually exclusive, suggested hypotheses. At the molecular level, recent studies have shown that most disease linked ASPA gene variants lead to a structural destabilization and subsequent proteasomal degradation of the ASPA protein variants, and accordingly Canavan disease should in general be considered a protein misfolding disorder. Here, we comprehensively summarize the molecular and cell biology of ASPA, with a particular focus on disease-linked gene variants and the pathophysiology of Canavan disease. We highlight the importance of high-throughput technologies and computational prediction tools for making genotype–phenotype predictions as we await the results of ongoing trials with gene therapy for Canavan disease.https://doi.org/10.1186/s13578-024-01224-6Protein foldingProtein stabilityProtein degradationProtein quality controlProtein misfoldingProteasome |
| spellingShingle | Martin Grønbæk-Thygesen Rasmus Hartmann-Petersen Cellular and molecular mechanisms of aspartoacylase and its role in Canavan disease Cell & Bioscience Protein folding Protein stability Protein degradation Protein quality control Protein misfolding Proteasome |
| title | Cellular and molecular mechanisms of aspartoacylase and its role in Canavan disease |
| title_full | Cellular and molecular mechanisms of aspartoacylase and its role in Canavan disease |
| title_fullStr | Cellular and molecular mechanisms of aspartoacylase and its role in Canavan disease |
| title_full_unstemmed | Cellular and molecular mechanisms of aspartoacylase and its role in Canavan disease |
| title_short | Cellular and molecular mechanisms of aspartoacylase and its role in Canavan disease |
| title_sort | cellular and molecular mechanisms of aspartoacylase and its role in canavan disease |
| topic | Protein folding Protein stability Protein degradation Protein quality control Protein misfolding Proteasome |
| url | https://doi.org/10.1186/s13578-024-01224-6 |
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