Kevin Haas
Last active: 2/12/2015

Profile

In my laboratory, our research focuses on understanding how targeted protein degradation by the ubiquitin proteasome system (UPS) regulates synaptic function and neuronal excitability in health and in neurodevelopmental disease. A primary mechanism through which synaptic strength is modulated is through changes in the number and composition of ionotropic glutamate and GABAA receptors, which are the principle mediators of fast excitatory and inhibitory neurotransmission in the brain. While there is strong evidence for UPS-mediated degradation of synaptic proteins, its role in modulating neuronal excitability through regulation of glutamate and GABAA receptor function has not been thoroughly explored. We utilize the Drosophila neuromuscular junction synapse to elucidate the time course and mechanisms of UPS-mediated postsynaptic regulation of glutamatergic synaptic function. We utilize cultured rat hippocampal neurons to examine UPS regulation of mammalian AMPA-type glutamate and GABAA receptors. We strive to translate the basic understanding of neuronal UPS mechanisms into treatments for Angelman syndrome, a devastating neurodevelopmental disease caused by UPS dysfunction. Angelman syndrome (AS) is characterized by severe developmental delay, near complete lack of expressive language development, ataxia of gait and limb movements, refractory epilepsy, and a characteristic happy demeanor. The most common cause of AS is a maternal deletion in the 15q11-13 chromosome region, but mutations in the UBE3A gene found within this region are sufficient to cause all of the phenotypic features of the disease. This gene codes for the Ube3A/E6-AP E3 ubiquitin ligase and is imprinted in the brain, with near complete paternal inactivation leading to maternal-dominated expression in neurons. Mice with knockout of the maternal UBE3A allele show behavioral and physiological similarities to the human AS, including motor incoordination, contextual learning deficits, impaired long-term potentiation, and a propensity for seizures. Epilepsy affects nearly all AS patients, and is frequently intractable, strongly impacting the quality of life for patients and their families. We are utilizing this AS mouse model to understand how Ube3A/E6-AP dysfunction leads to increased neuronal excitability and epilepsy. Also, we use this mouse model to test the effects of therapeutic interventions to restore normal synaptic function and correct neurobehavioral deficits in order to develop AS treatments. Moreover, we expect that these investigations will further the understanding of mechanisms of epileptogenesis and neurodevelopmental disease, providing critical insights into developing new therapies for epilepsy and autism spectrum disorders.

Publications

The following timeline graph is generated from all co-authored publications.

Featured publications are shown below:

  1. Cough syncope in a 43-year-old woman with glomus jugulare tumor. Bandyopadhyay S, Sonmezturk H, Abou-Khalil B, Haas KF (2014) Epilepsy Behav Case Rep : 124-6
    › Primary publication · 25667888 (PubMed) · PMC4307954 (PubMed Central)
  2. Inter-rater agreement on identification of electrographic seizures and periodic discharges in ICU EEG recordings. Halford JJ, Shiau D, Desrochers JA, Kolls BJ, Dean BC, Waters CG, Azar NJ, Haas KF, Kutluay E, Martz GU, Sinha SR, Kern RT, Kelly KM, Sackellares JC, LaRoche SM (2015) Clin Neurophysiol 126(9): 1661-9
    › Primary publication · 25481336 (PubMed) · PMC4439396 (PubMed Central)
  3. Non-convulsive status epilepticus and non-convulsive seizures in neurological ICU patients. Laccheo I, Sonmezturk H, Bhatt AB, Tomycz L, Shi Y, Ringel M, DiCarlo G, Harris D, Barwise J, Abou-Khalil B, Haas KF (2015) Neurocrit Care 22(2): 202-11
    › Primary publication · 25246236 (PubMed)
  4. Dosing feasibility and tolerability of intranasal diazepam in adults with epilepsy. Sperling MR, Haas KF, Krauss G, Seif Eddeine H, Henney HR, Rabinowicz AL, Bream G, Squillacote D, Carrazana EJ (2014) Epilepsia 55(10): 1544-50
    › Primary publication · 25154625 (PubMed)
  5. Tissue-specific variation of Ube3a protein expression in rodents and in a mouse model of Angelman syndrome. Gustin RM, Bichell TJ, Bubser M, Daily J, Filonova I, Mrelashvili D, Deutch AY, Colbran RJ, Weeber EJ, Haas KF (2010) Neurobiol Dis 39(3): 283-91
    › Primary publication · 20423730 (PubMed) · PMC2922926 (PubMed Central)
  6. Visual field defects after selective amygdalohippocampectomy and standard temporal lobectomy. Mengesha T, Abu-Ata M, Haas KF, Lavin PJ, Sun DA, Konrad PE, Pearson M, Wang L, Song Y, Abou-Khalil BW (2009) J Neuroophthalmol 29(3): 208-13
    › Primary publication · 19726943 (PubMed)
  7. Roles of ubiquitination at the synapse. Haas KF, Broadie K (2008) Biochim Biophys Acta 1779(8): 495-506
    › Primary publication · 18222124 (PubMed) · PMC2668815 (PubMed Central)
  8. Proteasome function is required to maintain muscle cellular architecture. Haas KF, Woodruff E, Broadie K (2007) Biol Cell 99(11): 615-26
    › Primary publication · 17523916 (PubMed) · PMC2712885 (PubMed Central)
  9. The ubiquitin-proteasome system postsynaptically regulates glutamatergic synaptic function. Haas KF, Miller SL, Friedman DB, Broadie K (2007) Mol Cell Neurosci 35(1): 64-75
    › Primary publication · 17363264 (PubMed) · PMC1936977 (PubMed Central)