Vanderbilt Kennedy Center

Kevin Haas, Ph.D., M.D.

Assistant Professor of Neurology
Member

Contact Info

Phone
(615) 936-6047

Email
kevin.haas@vanderbilt.edu

Address
6140 MRB III

Website

http://www.mc.vanderbilt.edu/neurology/faculty/haas.htm

Kevin Haas, Ph.D., M.D.

Overview

In Dr. Haas’s laboratory, 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. The laboratory utilizes the Drosophila neuromuscular junction synapse to elucidate the time course and mechanisms of UPS-mediated postsynaptic regulation of glutamatergic synaptic function. Cultured rat hippocampal neurons are utilized to examine UPS regulation of mammalian AMPA-type glutamate and GABAA receptors.

The laboratory strives 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. This AS mouse model is utilized to understand how Ube3A/E6-AP dysfunction leads to increased neuronal excitability and epilepsy. Also, this mouse model is used to test the effects of therapeutic interventions to restore normal synaptic function and correct neurobehavioral deficits in order to develop AS treatments. Moreover, the lab expects 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.

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