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Understanding the molecular and cellular basis of Angelman Syndrome

Projectomschrijving

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Titel: A disulphide bond in the E2 enzyme Pex4p modulates ubiquitin-conjugating activity
Titel: Dissociation of locomotor and cerebellar deficits in a murine Angelman syndrome model
Titel: Impaired Neurite Contact Guidance in Ubiquitin Ligase E3a (Ube3a)-Deficient Hippocampal Neurons on Nanostructured Substrates
Auteur: Tonazzini, I., Meucci, S., Van Woerden, G. M., Elgersma, Y., Cecchini, M.
Magazine: Advanced Healthcare Materials
Titel: Ube3a reinstatement identifies distinct developmental windows in a murine Angelman syndrome model
Titel: Treatment of Cognitive Deficits in Genetic Disorders: A Systematic Review of Clinical Trials of Diet and Drug Treatments
Titel: Interaction of SH-SY5Y Cells with Nanogratings During Neuronal Differentiation: Comparison with Primary Neurons
Auteur: Tonazzini, Ilaria, Cecchini, Alessandra, Elgersma, Ype, Cecchini, Marco
Magazine: Advanced Healthcare Materials
Titel: Deubiquitylase USP2 Regulates the LDLR Pathway by Counteracting the E3-Ubiquitin Ligase IDOL
Auteur: Nelson, Jessica K, Sorrentino, Vincenzo, Avagliano Trezza, Rossella, Heride, Claire, Urbe, Sylvie, Distel, Ben, Zelcer, Noam
Magazine: Circulation Research
Titel: Treatment of Neurodevelopmental Disorders in Adulthood
Auteur: Castren, E., Elgersma, Y., Maffei, L., Hagerman, R.
Magazine: Journal of Neuroscience
Titel: GABAergic Neuron-Specific Loss of Ube3a Causes Angelman Syndrome-Like EEG Abnormalities and Enhances Seizure Susceptibility
Auteur: Judson, Matthew C., Wallace, Michael L., Sidorov, Michael S., Burette, Alain C., Gu, Bin, van Woerden, Geeske M., King, Ian F., Han, Ji Eun, Zylka, Mark J., Elgersma, Ype, Weinberg, Richard J., Philpot, Benjamin D.
Magazine: Neuron
Titel: Ca2+/Calmodulin-dependent Protein Kinase II  ( CaMKII) Controls the Activity of the Dopamine Transporter: IMPLICATIONS FOR ANGELMAN SYNDROME
Auteur: Steinkellner, T., Yang, J.-W., Montgomery, T. R., Chen, W.-Q., Winkler, M.-T., Sucic, S., Lubec, G., Freissmuth, M., Elgersma, Y., Sitte, H. H., Kudlacek, O.
Magazine: Journal of Biological Chemistry
Titel: Neurodevelopmental disease: A molecular tightrope
Titel: The Role of UBE2A and UBE3A in Motor- and Cognitive Function
Auteur: C.F. Bruinsma
Titel: Dissociation of locomotor and cerebellar deficits in Ube3a mice
Auteur: Y. Elgersma
Titel: A critical role for UBE3A in brain development
Auteur: Y. Elgersma
Titel: Structural and functional analysis of Ube3a/E6AP
Auteur: B. Distel
Titel: Model Systems to study UBE3A/E6AP function
Auteur: B. Distel
Titel: Understanding the molecular mechanisms underlying Angelman Syndrome
Auteur: Ype Elgersma
Titel: Understanding the molecular mechanisms underlying Angelman Syndrome
Auteur: Ype Elgersma
Titel: UBE3 gene reinstatement identifies distinct treatment windows in a mouse model for Angelman syndrome
Auteur: Ype Elgersma
Titel: Understanding the molecular mechanisms underlying Angelman Syndrome
Auteur: Ype Elgersma

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Eindverslag

Angelman syndroom is een ernstige aangeboren neurologische aandoening. Het wordt veroorzaakt door mutaties in het Ube3a gen. Echter hoe deze mutaties kunnen leiden tot de ernstige neurologische problemen is niet bekend. We hebben onderzocht welke eiwitten in het brein door het UBE3a eiwit gereguleerd worden. Tevens hebben we gekeken wat de oorsprong is van de motor coördinatie problemen bij deze aandoening. Tenslotte hebben we een muismodel gecreëerd waarin we kunnen testen in hoeverre het Angelman syndroom omkeerbaar is.

Samenvatting van de aanvraag

Angelman syndrome (AS) is a severe neurological disorder, affecting 1:10,000-15,000 children. It is characterized by severe mental retardation, epilepsy, motor dysfunction and absence of speech. The disease is caused by the loss of a functional copy of the maternal UBE3A gene. Since the paternal UBE3A gene is silenced in the brain, such a mutation results in the complete absence of neuronal UBE3A expression. The UBE3A gene encodes the ubiquitin protein ligase E6AP, however since its identification 16 years ago, little progress has been made that provides insight in its role in neuronal function. Recent studies from our lab suggested that loss of E6AP results in the inhibition of CaMK2. CaMK2 plays a pivotal role in neuronal function, and preventing CaMK2 inhibition was indeed successful to rescue the neurological symptoms of an AS mouse model. However, the link between E6AP and CaMK2 regulation remains elusive, hampering the development of mechanism-based therapeutic strategies to ameliorate the neurological deficits of AS patients. It is even questionable if it is worthwhile to investigate in mechanism-based therapeutic strategies at all, since it is currently unknown to what extent the neurological symptoms are reversible, even if we were able to completely restore E6AP mediated signaling. This is a multi-disciplinary application from a neurobiology laboratory specialized in synaptic plasticity using mouse models, and from a biochemical laboratory specialized in protein-protein interaction and ubiquitination. Together, we seek to get insight in the most eminent questions concerning the mechanisms underlying Angelman syndrome: First, we will use three converging approaches to find candidate targets of E6AP (aim 1), and second, we will subsequently validate these targets using in vitro and in vivo approaches (aim 2). Third, the mechanism of the (brain specific) silencing of the paternal Ube3a allele is still unclear. In aim 3, we will directly test the most plausible hypothesis, i.e. that the paternal allele is silenced by an anti-sense transcript overlying the UBE3A gene. We will not only investigate how the paternal gene is silenced, but also why it needs to be silenced, by examining the effect of bi-allelic expression of the UBE3A gene on neuronal function. Fourth, we will test the role of E6AP in brain development as well as adult neuronal function by making use of inducible Ube3a mutants (aim 4). Since this allows us to switch the UBE3A gene on and off at any desirable age, we will be able to test to what extent the neurological symptoms are reversible. In addition these mouse models will be very valuable for E6AP target validation. Finally, we will use the existing and novel mouse models generated in this application, to investigate the role of E6AP in inhibitory neurons (aim 5). We are specifically interested to what extent the motor dysfunction is caused by cerebellar Purkinje cell dysfunction. We strongly believe that the proposed experiments will collectively make a very substantial contribution to understanding AS. Such a strong multi-disciplinary effort is required to get more insight in this devastating disorder.

Onderwerpen

Kenmerken

Projectnummer:
91209046
Looptijd: 100%
Looptijd: 100 %
2010
2016
Onderdeel van programma:
Gerelateerde subsidieronde:
Projectleider en penvoerder:
Prof. dr. Y. Elgersma
Verantwoordelijke organisatie:
Erasmus MC