Drosophila Ube3a regulates monoamine synthesis by increasing GTP cyclohydrolase I activity via a non-ubiquitin ligase mechanism
The underlying defects in Angelman syndrome (AS) and autism spectrum disorder (ASD) may be in part due to basic defects in synaptic plasticity and function. In some individuals serotonin reuptake inhibitors, which decrease pre-synaptic re-uptake of serotonin, can ameliorate symptoms, as can resperid...
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| Format: | Article |
| Language: | English |
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Elsevier
2011-03-01
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| Series: | Neurobiology of Disease |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996110003943 |
| _version_ | 1831547785905700864 |
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| author | Faiza Ferdousy William Bodeen Kyle Summers Olugbenga Doherty O'Neil Wright Nahed Elsisi George Hilliard Janis M. O'Donnell Lawrence T. Reiter |
| author_facet | Faiza Ferdousy William Bodeen Kyle Summers Olugbenga Doherty O'Neil Wright Nahed Elsisi George Hilliard Janis M. O'Donnell Lawrence T. Reiter |
| author_sort | Faiza Ferdousy |
| collection | DOAJ |
| description | The underlying defects in Angelman syndrome (AS) and autism spectrum disorder (ASD) may be in part due to basic defects in synaptic plasticity and function. In some individuals serotonin reuptake inhibitors, which decrease pre-synaptic re-uptake of serotonin, can ameliorate symptoms, as can resperidone, which blocks both dopamine and serotonin receptors. Loss of maternal UBE3A expression causes AS, while maternal duplications of chromosome 15q11.2–q13 that include the UBE3A gene cause ASD, implicating the maternally expressed UBE3A gene in the ASD phenotype. In a Drosophila screen for proteins regulated by UBE3A, we identified a key regulator of monoamine synthesis, the gene Punch, or GCH1, encoding the enzyme GTP cyclohydrolase I. Here we show that Dube3a, the fly UBE3A orthologue, regulates Punch/GCH1 in the fly brain. Over-expression of Dube3a elevates tetrahydrobiopterin (THB), the rate-limiting cofactor in monoamine synthesis while loss of Dube3a has the opposite effect. The fluctuations in dopamine levels were associated with hyper- and hypoactivity, respectively, in flies. We show that changes in Punch/GCH1 and dopamine levels do not depend on the ubiquitin ligase catalytic domain of Dube3a. In addition, both wild type Dube3a and a ubiquitination-defective Dube3a-C/A form were found at high levels in nuclear fractions and appear to be poly-ubiquitinated in vivo by endogenous Dube3a. We propose that the transcriptional co-activation function of Dube3a may regulate GCH1 activity in the brain. These results provide a connection between monoamine synthesis (dopamine/serotonin) and Dube3a expression that may explain why some individuals with ASD or AS respond better to selective serotonin reuptake inhibitors than others. |
| first_indexed | 2024-12-17T02:07:49Z |
| format | Article |
| id | doaj.art-b5e3372d0a5649779ce7405eb2c0210a |
| institution | Directory Open Access Journal |
| issn | 1095-953X |
| language | English |
| last_indexed | 2024-12-17T02:07:49Z |
| publishDate | 2011-03-01 |
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| series | Neurobiology of Disease |
| spelling | doaj.art-b5e3372d0a5649779ce7405eb2c0210a2022-12-21T22:07:38ZengElsevierNeurobiology of Disease1095-953X2011-03-01413669677Drosophila Ube3a regulates monoamine synthesis by increasing GTP cyclohydrolase I activity via a non-ubiquitin ligase mechanismFaiza Ferdousy0William Bodeen1Kyle Summers2Olugbenga Doherty3O'Neil Wright4Nahed Elsisi5George Hilliard6Janis M. O'Donnell7Lawrence T. Reiter8Department of Biology, University of Alabama, Box 870344, Tuscaloosa, AL 35487-0344, USADepartment of Neurology, University of Tennessee Health Science Center, 855 Monroe Ave., Memphis, TN 38163, USADepartment of Neurology, University of Tennessee Health Science Center, 855 Monroe Ave., Memphis, TN 38163, USADepartment of Biology, University of Alabama, Box 870344, Tuscaloosa, AL 35487-0344, USADepartment of Biology, University of Alabama, Box 870344, Tuscaloosa, AL 35487-0344, USADepartment of Neurology, University of Tennessee Health Science Center, 855 Monroe Ave., Memphis, TN 38163, USADepartment of Molecular Sciences, University of Tennessee Health Science Center, 855 Monroe Ave., Memphis, TN 38163, USADepartment of Biology, University of Alabama, Box 870344, Tuscaloosa, AL 35487-0344, USADepartment of Neurology, University of Tennessee Health Science Center, 855 Monroe Ave., Memphis, TN 38163, USA; Corresponding author. Department of Neurology, 855 Monroe Ave., Link 415, Memphis, TN 38163, USA. Fax: +1 901 448 7449.The underlying defects in Angelman syndrome (AS) and autism spectrum disorder (ASD) may be in part due to basic defects in synaptic plasticity and function. In some individuals serotonin reuptake inhibitors, which decrease pre-synaptic re-uptake of serotonin, can ameliorate symptoms, as can resperidone, which blocks both dopamine and serotonin receptors. Loss of maternal UBE3A expression causes AS, while maternal duplications of chromosome 15q11.2–q13 that include the UBE3A gene cause ASD, implicating the maternally expressed UBE3A gene in the ASD phenotype. In a Drosophila screen for proteins regulated by UBE3A, we identified a key regulator of monoamine synthesis, the gene Punch, or GCH1, encoding the enzyme GTP cyclohydrolase I. Here we show that Dube3a, the fly UBE3A orthologue, regulates Punch/GCH1 in the fly brain. Over-expression of Dube3a elevates tetrahydrobiopterin (THB), the rate-limiting cofactor in monoamine synthesis while loss of Dube3a has the opposite effect. The fluctuations in dopamine levels were associated with hyper- and hypoactivity, respectively, in flies. We show that changes in Punch/GCH1 and dopamine levels do not depend on the ubiquitin ligase catalytic domain of Dube3a. In addition, both wild type Dube3a and a ubiquitination-defective Dube3a-C/A form were found at high levels in nuclear fractions and appear to be poly-ubiquitinated in vivo by endogenous Dube3a. We propose that the transcriptional co-activation function of Dube3a may regulate GCH1 activity in the brain. These results provide a connection between monoamine synthesis (dopamine/serotonin) and Dube3a expression that may explain why some individuals with ASD or AS respond better to selective serotonin reuptake inhibitors than others.http://www.sciencedirect.com/science/article/pii/S0969996110003943UBE3AAngelman syndromeAutismDopamineGTPCH1Ubiquitin ligase activity |
| spellingShingle | Faiza Ferdousy William Bodeen Kyle Summers Olugbenga Doherty O'Neil Wright Nahed Elsisi George Hilliard Janis M. O'Donnell Lawrence T. Reiter Drosophila Ube3a regulates monoamine synthesis by increasing GTP cyclohydrolase I activity via a non-ubiquitin ligase mechanism Neurobiology of Disease UBE3A Angelman syndrome Autism Dopamine GTPCH1 Ubiquitin ligase activity |
| title | Drosophila Ube3a regulates monoamine synthesis by increasing GTP cyclohydrolase I activity via a non-ubiquitin ligase mechanism |
| title_full | Drosophila Ube3a regulates monoamine synthesis by increasing GTP cyclohydrolase I activity via a non-ubiquitin ligase mechanism |
| title_fullStr | Drosophila Ube3a regulates monoamine synthesis by increasing GTP cyclohydrolase I activity via a non-ubiquitin ligase mechanism |
| title_full_unstemmed | Drosophila Ube3a regulates monoamine synthesis by increasing GTP cyclohydrolase I activity via a non-ubiquitin ligase mechanism |
| title_short | Drosophila Ube3a regulates monoamine synthesis by increasing GTP cyclohydrolase I activity via a non-ubiquitin ligase mechanism |
| title_sort | drosophila ube3a regulates monoamine synthesis by increasing gtp cyclohydrolase i activity via a non ubiquitin ligase mechanism |
| topic | UBE3A Angelman syndrome Autism Dopamine GTPCH1 Ubiquitin ligase activity |
| url | http://www.sciencedirect.com/science/article/pii/S0969996110003943 |
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