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PhD Proposal Exam – Zahra Dargaei (Woodin lab)
April 27, 2016 @ 10:10 am - 11:10 am
PhD Proposal Exam
Wednesday April 27th, 10:10 am – Ramsay Wright Building, Rm. RW432
Zahra Dargaei (Woodin lab)
“Aberrant Chloride Homeostasis and Inhibitory Synaptic Transmission in Huntington’s Disease“
Abstract
Proper GABAA-mediated synaptic inhibition requires low levels of neuronal Cl– that is mainly achieved by the K+-Cl– cotransporter, KCC2. When KCC2 expression decreases, the neuronal Cl– gradient collapses and there is a profound reduction in synaptic inhibition. Reduced inhibition can reduce the inhibition-excitation balance, which can contribute to the development and symptoms of neurological disorders such as epilepsy. Huntington’s disease (HD) is a progressive hereditary brain disorder. It is a devastating disease for which there is currently no effective treatment. Early signs of the disease include depression, uncontrolled movements, and loss of memory. The disease is caused by mutations in the Huntingtin protein (Htt). Recent studies have screened for Htt interacting proteins and demonstrated a map of the Htt protein’s cellular partners. Interestingly, the proteomic interactome of Htt revealed that the KCC2 encoding gene, Slc12a5, is highly enriched in the Htt proteome, and this interaction appears to decrease when Htt is mutated. However, despite the strong correlation between KCC2 and Htt, this interaction and the possible role of KCC2 in HD has not been examined experimentally. Based on the critical role of KCC2 in neurophysiological function, and the reported decease in KCC2 interaction with Htt in HD, I propose that KCC2 function is compromised in HD brain. Thus, the focus of my PhD project is to determine whether KCC2 interacts with Htt and investigate whether this interaction is associated with HD pathology using a combination of biochemical, imaging, and electrophysiological assays in both mammalian cell expression systems and transgenic mice. Characterizing KCC2: Htt interaction will be the first study to demonstrate a clear link between KCC2 and neurodegenerative disease and could reveal novel molecular targets that can be used therapeutically to enhance KCC2 function and possibly restore aberrant synaptic transmission in HD brain.
Ramsay Wright is a wheelchair accessible building.