Abstract
Canavan disease (CD) is an autosomal recessive leukodystrophy characterized by spongy degeneration of the brain. The clinical features of CD are hypotonia, megalencephaly, and mental retardation leading to early death. While aspartoacylase (ASPA) activity increases with age in the wild type mouse brain, there is no ASPA activity in the CD mouse brain. So far ASPA deficiency and elevated NAA have been ascribed with the CD. Other factors affecting the brain that result from ASPA deficiency may lead pathophysiology of CD. The NMR spectra and amino acid analysis showed lower levels of glutamate and gamma-aminobutyric acid in the CD mouse brain compared to the wild type. Microarray gene expression on CD mouse brain showed glutamate transporter-EAAT4 and gamma-aminobutyric acid-A receptor, subunit alpha6 (GABRA6) were lower 9.7- and 119.1-fold, respectively. Serine proteinase inhibitor 2 (Spi2) was 29.9-fold higher in the CD mouse brain compared to the wild type. The decrease of GABRA6 and high expression of Spi2 in CD mouse brain were also confirmed by real-time RT-PCR. This first report showing abnormal expression of EAAT4, GABRA6, Spi2 combined with lower levels of glutamate and GABA are likely to be associated with the pathophysiology of CD.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Amino Acid Transport System X-AG / biosynthesis*
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Amino Acid Transport System X-AG / genetics
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Analysis of Variance
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Animals
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Azo Compounds / analysis
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Brain Chemistry
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Canavan Disease / genetics
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Canavan Disease / metabolism*
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Creatine / analysis
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Dipeptides / analysis
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Disease Models, Animal
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Glutamic Acid / analysis
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Glutamic Acid / metabolism*
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In Vitro Techniques
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Insect Proteins / biosynthesis*
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Insect Proteins / genetics
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Magnetic Resonance Spectroscopy / instrumentation
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Magnetic Resonance Spectroscopy / methods
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Mice
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Mice, Knockout
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Oligonucleotide Array Sequence Analysis / instrumentation
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Oligonucleotide Array Sequence Analysis / methods
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RNA, Messenger / biosynthesis
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Receptors, GABA-A / biosynthesis*
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Receptors, GABA-A / genetics
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Reverse Transcriptase Polymerase Chain Reaction / methods
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Sequence Analysis, Protein
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gamma-Aminobutyric Acid / classification
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gamma-Aminobutyric Acid / metabolism*
Substances
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Amino Acid Transport System X-AG
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Azo Compounds
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Dipeptides
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Gabra6 protein, mouse
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Insect Proteins
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RNA, Messenger
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Receptors, GABA-A
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silk proteinase inhibitor 2, Galleria mellonella
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isospaglumic acid
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lac dye
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Glutamic Acid
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gamma-Aminobutyric Acid
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Creatine