Faculty Appointments
Professor of Neurology
Education
M.D., Medicine, University of Michigan, Ann Arbor, MichiganPh.D., Neuroscience, University of Michigan, Ann Arbor, MichiganB.S., Biomedical Engineering, Duke University, Durham, North Carolina
Office Address
6140 MRB III
465 21st Avenue South
Nashville, TN 37212-8552
465 21st Avenue South
Nashville, TN 37212-8552
Research Description
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.
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.
Research Keywords
Epilepsy and Angelman syndrome.
Clinical Research Keywords
epilepsy
Publications
Haas KF, Broadie K. Roles of ubiquitination at the synapse. Biochim. Biophys. Acta [print-electronic]. 2008 Aug; 1779(8): 495-506. PMID: 18222124, PMCID: PMC2668815, PII: S1874-9399(07)00203-9, DOI: 10.1016/j.bbagrm.2007.12.010, ISSN: 0006-3002.
Haas KF, Woodruff E, Broadie K. Proteasome function is required to maintain muscle cellular architecture. Biol. Cell. 2007 Nov; 99(11): 615-26. PMID: 17523916, PMCID: PMC2712885, PII: BC20070019, DOI: 10.1042/BC20070019, ISSN: 1768-322X.
Bianchi MT, Botzolakis EJ, Haas KF, Fisher JL, Macdonald RL. Microscopic kinetic determinants of macroscopic currents: insights from coupling and uncoupling of GABAA receptor desensitization and deactivation. J. Physiol. (Lond.) [print-electronic]. 2007 Nov 11/1/2007; 584(Pt 3): 769-87. PMID: 17884921, PMCID: PMC2276985, PII: jphysiol.2007.142364, DOI: 10.1113/jphysiol.2007.142364, ISSN: 0022-3751.
Haas KF, Miller SL, Friedman DB, Broadie K. The ubiquitin-proteasome system postsynaptically regulates glutamatergic synaptic function. Mol. Cell. Neurosci [print-electronic]. 2007 May; 35(1): 64-75. PMID: 17363264, PMCID: PMC1936977, PII: S1044-7431(07)00027-9, DOI: 10.1016/j.mcn.2007.02.002, ISSN: 1044-7431.
Bianchi MT, Haas KF, Macdonald RL. Alpha1 and alpha6 subunits specify distinct desensitization, deactivation and neurosteroid modulation of GABA(A) receptors containing the delta subunit. Neuropharmacology. 2002 Sep; 43(4): 492-502. PMID: 12367596, PII: S0028390802001636, ISSN: 0028-3908.
Bianchi MT, Haas KF, Macdonald RL. Structural determinants of fast desensitization and desensitization-deactivation coupling in GABAa receptors. J. Neurosci. 2001 Feb 2/15/2001; 21(4): 1127-36. PMID: 11160383, PII: 21/4/1127, ISSN: 1529-2401.
Burgard EC, Haas KF, Macdonald RL. Channel properties determine the transient activation kinetics of recombinant GABA(A) receptors. Brain Res. Mol. Brain Res. 1999 Nov 11/10/1999; 73(1-2): 28-36. PMID: 10581395, PII: S0169328X99002302, ISSN: 0169-328X.
Kapur J, Haas KF, Macdonald RL. Physiological properties of GABAA receptors from acutely dissociated rat dentate granule cells. J. Neurophysiol. 1999 May; 81(5): 2464-71. PMID: 10322081, ISSN: 0022-3077.
Haas KF, Macdonald RL. GABAA receptor subunit gamma2 and delta subtypes confer unique kinetic properties on recombinant GABAA receptor currents in mouse fibroblasts. J. Physiol. (Lond.). 1999 Jan 1/1/1999; 514 ( Pt 1): 27-45. PMID: 9831714, PMCID: PMC2269054, ISSN: 0022-3751.
Agrawal CM, Haas KF, Leopold DA, Clark HG. Evaluation of poly(L-lactic acid) as a material for intravascular polymeric stents. Biomaterials. 1992; 13(3): 176-82. PMID: 1567942, PII: 0142-9612(92)90068-Y, ISSN: 0142-9612.
Haas KF, Woodruff E, Broadie K. Proteasome function is required to maintain muscle cellular architecture. Biol. Cell. 2007 Nov; 99(11): 615-26. PMID: 17523916, PMCID: PMC2712885, PII: BC20070019, DOI: 10.1042/BC20070019, ISSN: 1768-322X.
Bianchi MT, Botzolakis EJ, Haas KF, Fisher JL, Macdonald RL. Microscopic kinetic determinants of macroscopic currents: insights from coupling and uncoupling of GABAA receptor desensitization and deactivation. J. Physiol. (Lond.) [print-electronic]. 2007 Nov 11/1/2007; 584(Pt 3): 769-87. PMID: 17884921, PMCID: PMC2276985, PII: jphysiol.2007.142364, DOI: 10.1113/jphysiol.2007.142364, ISSN: 0022-3751.
Haas KF, Miller SL, Friedman DB, Broadie K. The ubiquitin-proteasome system postsynaptically regulates glutamatergic synaptic function. Mol. Cell. Neurosci [print-electronic]. 2007 May; 35(1): 64-75. PMID: 17363264, PMCID: PMC1936977, PII: S1044-7431(07)00027-9, DOI: 10.1016/j.mcn.2007.02.002, ISSN: 1044-7431.
Bianchi MT, Haas KF, Macdonald RL. Alpha1 and alpha6 subunits specify distinct desensitization, deactivation and neurosteroid modulation of GABA(A) receptors containing the delta subunit. Neuropharmacology. 2002 Sep; 43(4): 492-502. PMID: 12367596, PII: S0028390802001636, ISSN: 0028-3908.
Bianchi MT, Haas KF, Macdonald RL. Structural determinants of fast desensitization and desensitization-deactivation coupling in GABAa receptors. J. Neurosci. 2001 Feb 2/15/2001; 21(4): 1127-36. PMID: 11160383, PII: 21/4/1127, ISSN: 1529-2401.
Burgard EC, Haas KF, Macdonald RL. Channel properties determine the transient activation kinetics of recombinant GABA(A) receptors. Brain Res. Mol. Brain Res. 1999 Nov 11/10/1999; 73(1-2): 28-36. PMID: 10581395, PII: S0169328X99002302, ISSN: 0169-328X.
Kapur J, Haas KF, Macdonald RL. Physiological properties of GABAA receptors from acutely dissociated rat dentate granule cells. J. Neurophysiol. 1999 May; 81(5): 2464-71. PMID: 10322081, ISSN: 0022-3077.
Haas KF, Macdonald RL. GABAA receptor subunit gamma2 and delta subtypes confer unique kinetic properties on recombinant GABAA receptor currents in mouse fibroblasts. J. Physiol. (Lond.). 1999 Jan 1/1/1999; 514 ( Pt 1): 27-45. PMID: 9831714, PMCID: PMC2269054, ISSN: 0022-3751.
Agrawal CM, Haas KF, Leopold DA, Clark HG. Evaluation of poly(L-lactic acid) as a material for intravascular polymeric stents. Biomaterials. 1992; 13(3): 176-82. PMID: 1567942, PII: 0142-9612(92)90068-Y, ISSN: 0142-9612.