Angelman syndrome


Angelman syndrome is a severe genetic disorder caused by mutations or deletions of the maternally inherited UBE3A gene. UBE3A encodes an E3 ubiquitin ligase that is expressed biallelically in most tissues but is maternally expressed in almost all neurons. Patients with AS exhibit developmental delay, speech impairments, intellectual disability, epilepsy, abnormal EEGs (electroencephalograms), puppet-like ataxic movements, prognathism, tongue protrusion, paroxysms of laughter, abnormal sleep patterns, and hyperactivity (Mabb et al., 2011).

The Philpot group takes a multidisciplinary approach to understand molecular and physiological mechanisms underlying AS and to identify potential therapeutic targets.

 We focus on:
  • Drug discovery
  • Functional activity in visual cortex
  • Experience-dependent plasticity in vivo
  • Structural plasticity in vivo
  • Seizure susceptibility and epileptogenesis
  • The neurobiological mechanisms underlying sleep disturbances
  • Excitatory / inhibitory imbalance in forebrain circuits

Key publications:

Judson, M. C., Burette, A. C., Thaxton, C. L., Pribisko, A. L., Shen, M. D., Rumple, A. M., . . . Philpot, B. D. (2017). Decreased Axon Caliber Underlies Loss of Fiber Tract Integrity, Disproportional Reductions in White Matter Volume, and Microcephaly in Angelman Syndrome Model Mice. J Neurosci, 37(31), 7347-7361. doi:10.1523/JNEUROSCI.0037-17.2017

Sidorov MS, Deck GM, Dolatshahi M, Bird LM, Thibert RL, Chu CJ, and Philpot BD (2017).  Delta rhythmicity is a reliable biomarker in Angelman syndrome: a parallel mouse and human analysisJ Neurodev Dis 9:17.

Jones KA, Han JE, DeBruyne JP, Philpot BD (2016) Persistent neuronal Ube3a expression in the suprachiasmatic nucleus of Angelman syndrome model mice. Scientific Reports 6:28238.

Kim H, Kunz PA, Mooney R, Philpot BD,  Smith SL. Maternal Loss of Ube3a Impairs Experience-Driven Dendritic Spine Maintenance in the Developing Visual Cortex. J Neurosci, 2016 Apr 27;36(17), 4888-4894. doi: 10.1523/JNEUROSCI.4204-15.2016

Judson MC, Wallace ML, Sidorov MS, Burette AC, Gu B, van Woerden GM, King IF, Han JE, Zylka MJ, Elgersma Y, Weinberg RJ, Philpot BD GABAergic neuron-specific loss of Ube3a causes Angelman syndrome-like EEG abnormalities and enchances seizure susceptibility.  Neuron. 2016 Apr 6;doi:10.1016/j.neuron.2016.02.040

Berrios J, Stamatakis AM, Kantak PA, McElligott ZA, Judson MC, Aita M, Rougie M, Stuber GD, Philpot BDLoss of UBE3A from TH-expressing neurons suppresses GABA co-release and enhances VTA-NAc optical self-stimulation. Nat Commun. 2016 Feb 12;7:10702. doi: 10.1038/ncomms10702.

Ehlen JC, Jones KA, Pinckney L, Gray CL, Burette S, Weinberg RJ, Evans JA, Brager AJ, Zylka MJ, Paul KN, Philpot BD, DeBruyne JP. Maternal Ube3a Loss Disrupts Sleep Homeostasis But Leaves Circadian Rhythmicity Largely Intact. J Neurosci. 2015 Oct 7;35(40):13587-98. doi: 10.1523/JNEUROSCI.2194-15.2015.

Yi JJ, Berrios J, Newbern JM, Snider WD, Philpot BD, Hahn KM, Zylka MJ. An Autism-Linked Mutation Disables Phosphorylation Control of UBE3A. Cell. 2015 Aug 13;162(4):795-807. doi: 10.1016/j.cell.2015.06.045. Epub 2015 Aug 6.

Judson MC, Sosa-Pagan JO, Delcid WA, Han JE, Philpot BD. Allelic specificity of Ube3a expression in the mouse brain during postnatal development.   J Comp Neurol. 2013 Nov 20.

Huang HS, Burns AJ, Nonneman RJ, Baker LK, Riddick NV, Nikolova VD, Riday TT, Yashiro K,Philpot BD, Moy SS. Behavioral deficits in an Angelman syndrome model: effects of genetic background and age. Behav Brain Res. 2013 Apr 15;243:79-90. doi: 10.1016/j.bbr.2012.12.052. Epub 2013 Jan 4.

Riday TT, Dankoski EC, Krouse MC, Fish EW, Walsh PL, Han JE, Hodge CW, Wightman RM, Philpot BD, Malanga CJ. Pathway-specific dopaminergic deficits in a mouse model of Angelman syndrome. J Clin Invest. 2012 Dec 3;122(12):4544-54

Wallace ML, Burette AC, Weinberg RJ, Philpot BD. Maternal loss of Ube3a produces an excitatory/inhibitory imbalance through neuron type-specific synaptic defects. Neuron. 2012 Jun 7;74(5):793-800.

Huang HS, Allen JA, Mabb AM, King IF, Miriyala J, Taylor-Blake B, Sciaky N, Dutton JW Jr, Lee HM, Chen X, Jin J, Bridges AS, Zylka MJ, Roth BL, Philpot BD.Topoisomerase inhibitors unsilence the dormant allele of Ube3a in neurons.Nature. 2011 Dec 21;481(7380):185-9. doi: 10.1038/nature10726.

Mabb AM, Judson MC, Zylka MJ, Philpot BD. Angelman syndrome: insights into genomic imprinting and neurodevelopmental phenotypes. Trends Neurosci. 2011 Jun;34(6):293-303. doi: 10.1016/j.tins.2011.04.001. Epub 2011 May 17. Review.

Philpot BD, Thompson CE, Franco L, Williams CA. Angelman syndrome: advancing the research frontier of neurodevelopmental disorders. J Neurodev Disord. 2011 Mar;3(1):50-6. doi: 10.1007/s11689-010-9066-z. Epub 2010 Dec 3.

Yashiro K, Riday TT, Condon KH, Roberts AC, Bernardo DR, Prakash R, Weinberg RJ, Ehlers MD, Philpot BD. Ube3a is required for experience-dependent maturation of the neocortex. Nat Neurosci. 2009 May 10. [Epub ahead of print]