Drosophila Ube3a regulates monoamine synthesis by increasing GTP cyclohydrolase I activity via a non-ubiquitin ligase mechanism
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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.
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In Drosophila, overexpression or genetic knockout of the Drosophila homolog of Ube3a respectively increased or decreased DA levels, potentially due to changes in the expression of tetrahydrobiopterin, the rate-limiting cofactor in monoamine synthesis in flies.
“In elegant genetic studies using the fruit-fly Drosophila, overexpression or genetic knockout of the Drosophila homolog of Ube3a respectively increased or decreased DA levels, potentially due to changes in the expression of tetrahydrobiopterin, the rate-limiting cofactor in monoamine synthesis in flies [696].”
From Reward circuitry dysfunction in psychiatric and neurodevelopmental disorders and genetic syndromes: animal models and clinical findings (2012) · cites this paper as [696]
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Cites
Targeted gene expression as a means of altering cell fates and generating dominant phenotypes
Brand, A. H., & Perrimon, N. (1993) · Development · doi:10.1242/dev.118.2.401 · Cited by 9,510 · see citing works
Nagatsu, T., Levitt, M., & Udenfriend, S. (1964) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)93832-9 · Cited by 2,067 · see citing works
UBE3A/E6-AP mutations cause Angelman syndrome
Kishino, T., Lalande, M., & Wagstaff, J. E. (1997) · Nature Genetics · doi:10.1038/ng0197-70 · Cited by 1,304 · see citing works
Protein regulation by monoubiquitin
Hicke, L. (2001) · Nature Reviews Molecular Cell Biology · doi:10.1038/35056583 · Cited by 1,213 · see citing works
GAL4 system in drosophila: A fly geneticist's swiss army knife
Duffy, J. B. (2002) · genesis · doi:10.1002/gene.10150 · Cited by 1,099 · see citing works
Tetrahydrobiopterin biosynthesis, regeneration and functions
Thöny, B., Auerbach, G., & Blau, N. (2000) · Biochemical Journal · doi:10.1042/bj3470001 · Cited by 867 · see citing works
Albrecht, U., Sutcliffe, J. S., Cattanach, B. M., BEECHEY, C. V., Armstrong, D. L., Gregor Eichele, C., & Beaudet, A. L. (1997) · Nature Genetics · doi:10.1038/ng0997-75 · Cited by 586 · see citing works
Udenfriend, S. (1966) · Pharmacological Reviews · doi:10.1016/s0031-6997(25)07173-x · Cited by 503 · see citing works
Dindot, S. V., Antalffy, B. A., Bhattacharjee, M. B., & Beaudet, A. L. (2007) · Human Molecular Genetics · doi:10.1093/hmg/ddm288 · Cited by 418 · see citing works
The Angelman syndrome candidate gene, UBE3AIE6-AP, is imprinted in brain
Rougeulle, C., Glatt, H., & Lalande, M. (1997) · Nature Genetics · doi:10.1038/ng0997-14 · Cited by 416 · see citing works
Huibregtse, J. M., Scheffner, M., & Howley, P. M. (1993) · Molecular and Cellular Biology · doi:10.1128/mcb.13.8.4918 · Cited by 395 · see citing works
Autism and maternally derived aberrations of chromosome 15q
Schroer, R. J., Phelan, M. C., Michaelis, R. C., Crawford, E. C., Skinner, S. A., Cuccaro, M. L., Simensen, R. J., Bishop, J., Skinner, C. D., Fender, D., et al. (1998) · American Journal of Medical Genetics · doi:10.1002/(sici)1096-8628(19980401)76:4 · Cited by 375 · see citing works
The comorbidity of autism with the genomic disorders of chromosome 15q11.2-q13
Hogart, A., Wu, D., LaSalle, J. M., & Schanen, N. C. (2008) · Neurobiology of Disease · doi:10.1016/j.nbd.2008.08.011 · Cited by 354 · see citing works
Ube3a is required for experience-dependent maturation of the neocortex
Yashiro, K., Riday, T. T., Condon, K. H., Roberts, A. C., Bernardo, D. R., Prakash, R., Weinberg, R. J., Ehlers, M. D., & Philpot, B. D. (2009) · Nature Neuroscience · doi:10.1038/nn.2327 · Cited by 328 · see citing works
Noradrenaline: Fate and Control of Its Biosynthesis
Axelrod, J. (1971) · Science · doi:10.1126/science.173.3997.598 · Cited by 291 · see citing works
Autism spectrum disorders in Prader???Willi and Angelman syndromes: a systematic review
Veltman, M. W. M., Craig, E. E., & Bolton, P. (2005) · Psychiatric Genetics · doi:10.1097/00041444-200512000-00006 · Cited by 218 · see citing works
Watson, P., Black, G. C. M., Ramsden, S., Barrow, M., Super, M., Kerr, B. A., & Clayton‐Smith, J. (2001) · Journal of Medical Genetics · doi:10.1136/jmg.38.4.224 · Cited by 210 · see citing works
Interaction of Genetic and Environmental Factors in aDrosophilaParkinsonism Model
Chaudhuri, A., Bowling, K. M., Funderburk, C. D., et al. (2007) · Journal of Neuroscience · doi:10.1523/jneurosci.4239-06.2007 · Cited by 204 · see citing works
Jiang, Y.-H., Lev-Lehman, E., Bressler, J., Tsai, T., & Beaudet, A. L. (1999) · The American Journal of Human Genetics · doi:10.1086/302473 · Cited by 199 · see citing works
Selective Serotonin Reuptake Inhibitors in Autism
Kolevzon, A. L., Mathewson, K. A., & Hollander, E. (2006) · The Journal of Clinical Psychiatry · doi:10.4088/jcp.v67n0311 · Cited by 176 · see citing works
Serotonin and dopamine transporter binding in children with autism determined by SPECT
Makkonen, I., Riikonen, R., Kokki, H., Airaksinen, M. M., & Kuikka, J. T. (2008) · Developmental Medicine & Child Neurology · doi:10.1111/j.1469-8749.2008.03027.x · Cited by 169 · see citing works
Huibregtse, J. M., Scheffner, M., & Howley, P. M. (1993) · Molecular and Cellular Biology · doi:10.1128/mcb.13.8.4918-4927.1993 · Cited by 157 · see citing works
Molecular epigenetics of Angelman syndrome
Lalande, M., & Calciano, M. A. (2007) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-007-6460-0 · Cited by 149 · see citing works
The trace amine tyramine is essential for sensitization to cocaine in Drosophila
McClung, C. A., & Hirsh, J. (1999) · Current Biology · doi:10.1016/s0960-9822(99)80389-3 · Cited by 149 · see citing works
Drosophila Tyrosine Hydroxylase is Encoded by the Pale Locus
Neckameyer, W. S., & White, K. (1993) · Journal of Neurogenetics · doi:10.3109/01677069309083448 · Cited by 137 · see citing works
Pendleton, R. G., Rasheed, A., Sardina, T., Tully, T., & Hillman, R. (2002) · Behavior Genetics · doi:10.1023/a:1015279221600 · Cited by 120 · see citing works
Carbone, M. A., Jordan, K. W., Lyman, R. F., et al. (2006) · Current Biology · doi:10.1016/j.cub.2006.03.051 · Cited by 109 · see citing works
E6-associated protein (E6-AP) is a dual function coactivator of steroid hormone receptors
Ramamoorthy, S., & Nawaz, Z. (2008) · Nuclear Receptor Signaling · doi:10.1621/nrs.06006 · Cited by 109 · see citing works
Behavior and neuropsychiatric manifestations in Angelman syndrome
Dan, B. (2008) · Neuropsychiatric Disease and Treatment · doi:10.2147/ndt.s2749 · Cited by 108 · see citing works
Expression of the Rho-GEF Pbl/ECT2 is regulated by the UBE3A E3 ubiquitin ligase
Reiter, L. T., Seagroves, T. N., Bowers, M., & Bier, E. (2006) · Human Molecular Genetics · doi:10.1093/hmg/ddl225 · Cited by 102 · see citing works
Self-citationA Drosophila model for Angelman syndrome
Wu, Y., Bolduc, F. V., Bell, K., Tully, T., Fang, Y., Sehgal, A., & Fischer, J. A. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0805291105 · Cited by 100 · see citing works
Increased Dopamine Level Enhances Male–Male Courtship inDrosophila
Liu, T., Dartevelle, L., Yuan, C., Wei, H., Wang, Y., Ferveur, J., & Guo, A. (2008) · Journal of Neuroscience · doi:10.1523/jneurosci.5290-07.2008 · Cited by 95 · see citing works
Descheemaeker, M., Govers, V., Vermeulen, P., & Fryns, J. (2006) · American Journal of Medical Genetics Part A · doi:10.1002/ajmg.a.31235 · Cited by 95 · see citing works
Hettinger, J. A., Liu, X., Schwartz, C. E., Michaelis, R. C., & Holden, J. J. A. (2008) · American Journal of Medical Genetics Part B Neuropsychiatric Genetics · doi:10.1002/ajmg.b.30655 · Cited by 86 · see citing works
Two percent of patients suspected of having Angelman syndrome have TCF4 mutations
Takano, K., Lyons, M. J., Moyes, C. D., Jones, J. R., & Schwartz, C. (2010) · Clinical Genetics · doi:10.1111/j.1399-0004.2010.01380.x · Cited by 86 · see citing works
Baron, C. A., Tepper, C. G., Liu, S. Y., Davis, R. R., Wang, N. J., Schanen, N. C., & Gregg, J. P. (2006) · Human Molecular Genetics · doi:10.1093/hmg/ddl004 · Cited by 80 · see citing works
Canitano, R. (2008) · Neuropsychiatric Disease and Treatment · doi:10.2147/ndt.s1450 · Cited by 74 · see citing works
Loss of dopaminergic neurons and resulting behavioural deficits in mouse model of Angelman syndrome
Mulherkar, S. A., & Jana, N. R. (2010) · Neurobiology of Disease · doi:10.1016/j.nbd.2010.08.002 · Cited by 71 · see citing works
Roles of ubiquitination at the synapse
Haas, K. F., & Broadie, K. (2008) · Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms · doi:10.1016/j.bbagrm.2007.12.010 · Cited by 64 · see citing works
Mackay, W. J., & O’Donnell, J. M. (1983) · Genetics · doi:10.1093/genetics/105.1.35 · Cited by 63 · see citing works
Self-citationColas, J., Launay, J., & Maroteaux, L. (1999) · Mechanisms of Development · doi:10.1016/s0925-4773(99)00140-9 · Cited by 59 · see citing works
Decrease in 6R-5,6,7,8-tetrahydrobiopterin content in cerebrospinal fluid of autistic patients
Tani, Y., Fernell, E., Watanabe, Y., Kanai, T., & Långström, B. (1994) · Neuroscience Letters · doi:10.1016/0304-3940(94)90586-x · Cited by 54 · see citing works
Purification and characterization of GTP cyclohydrolase I from Drosophila melanogaster.
Weisberg, E. P., & O’Donnell, J. M. (1986) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(17)36114-8 · Cited by 51 · see citing works
Self-citationDrosophila dopamine synthesis pathway genes regulate tracheal morphogenesis
Hsouna, A., Lawal, H. O., Izevbaye, I., Hsu, T., & O’Donnell, J. M. (2007) · Developmental Biology · doi:10.1016/j.ydbio.2007.04.047 · Cited by 44 · see citing works
Self-citationFunctional Interactions Between GTP Cyclohydrolase I and Tyrosine Hydroxylase inDrosophila
Krishnakumar, S., Burton, D. Y., Rasco, J. F., et al. (2000) · Journal of Neurogenetics · doi:10.3109/01677060009083474 · Cited by 42 · see citing works
McLean, J. R., Krishnakumar, S., & O’Donnell, J. M. (1993) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(19)74237-9 · Cited by 39 · see citing works
Self-citationTISSUE-SPECIFIC AND COMPLEX COMPLEMENTATION PATTERNS IN THE PUNCH LOCUS OF DROSOPHILA MELANOGASTER
Mackay, W. J., Reynolds, E., & O’Donnell, J. M. (1985) · Genetics · doi:10.1093/genetics/111.4.885 · Cited by 27 · see citing works
Self-citationGenome-wide gene expression profiling of the Angelman syndrome mice with Ube3a mutation
Low, D., & Chen, K. (2010) · European Journal of Human Genetics · doi:10.1038/ejhg.2010.95 · Cited by 26 · see citing works
Funderburk, C. D., Bowling, K. M., Xu, D., et al. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m602196200 · Cited by 24 · see citing works
Another Patient With MECP2 Mutation Without Classic Rett Syndrome Phenotype
Milani, D., Pantaleoni, C., D’Arrigo, S., Selicorni, A., & Riva, D. (2005) · Pediatric Neurology · doi:10.1016/j.pediatrneurol.2004.12.012 · Cited by 22 · see citing works
Biochemical Conservation of Recombinant Drosophila Tyrosine Hydroxylase with its Mammalian Cognates
Neckameyer, W. S., Holt, B., & Paradowski, T. (2005) · Biochemical Genetics · doi:10.1007/s10528-005-6781-3 · Cited by 18 · see citing works
High-Throughput Proteomics Processing of Proteins in Polyacrylamide in a Multiwell Format
Cummings, E. D., Brown, J. M., Sarva, S. T., et al. (2007) · Journal of Proteome Research · doi:10.1021/pr060472y · Cited by 11 · see citing works
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- Peterson A Reiter L Genetic screen for potential protein substrates of the Drosophila E3 ubiquitin ligase gene (dube3a) 47th Annual Drosophila Research Conference Houston, TX 2006
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Dichter, G. S., Damiano, C. A., & Allen, J. A. (2012) · Journal of Neurodevelopmental Disorders · doi:10.1186/1866-1955-4-19 · Cited by 299 · see citing works
Smith, S. E. P., Zhou, Y.-D., Zhang, G., Jin, Z., Stoppel, D. C., & Anderson, M. P. (2011) · Science Translational Medicine · doi:10.1126/scitranslmed.3002627 · Cited by 267 · see citing works
- Authors
- Ferdousy, F., Bodeen, W., Summers, K., Doherty, O., Wright, O., Elsisi, N., Hilliard, G., O'Donnell, J. M., & Reiter, L. T.
- Affiliations
- University of Alabama (US)
- University of Tennessee Health Science Center (US)
- Corresponding author
- Reiter, Lawrence T.
- Venue
- Neurobiology of Disease
- Publisher
- Elsevier BV
- Published
- 2011-03
- Volume
- 41
- Issue
- 3
- Pages
- 669-677
- ISSN
- 0969-9961 (ISSN-L)
- PMC
- PMC3040417
- OpenAlex
- W1993275955
- Cited by
- 43
- References
- 52
- Citations by year
- 2026: 2 · 2024: 5 · 2023: 1 · 2021: 3 · 2020: 1 · 2019: 6 · 2018: 3 · 2017: 4 · 2016: 2 · 2015: 3 · 2014: 2 · 2013: 3 · 2012: 5
- FWCI
- 1.42
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Neurobiology of Disease (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Autism Speaks
- Angelman Syndrome Foundation
- National Institute of Neurological Disorders and Stroke (R01NS059902)
- University of Alabama
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurobiology and Insect Physiology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Keywords
- UBE3A, GTP cyclohydrolase I, punch, monoamine synthesis, tetrahydrobiopterin, dopamine, serotonin, Angelman syndrome, autism spectrum disorder, ubiquitination, transcriptional coactivation, synaptic plasticity, serotonin reuptake inhibitors, Drosophila
- MeSH terms
- Animals, Dopamine, Drosophila, Enzyme Activation, Female, GTP Cyclohydrolase, Humans, Male, Mutation, Serotonin, Up-Regulation, Drosophila Proteins, Animals, Genetically Modified, Ubiquitin-Protein Ligases
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