There are many different underlying causes of epilepsy and associated neurodegeneration, most of which are still unknown. Identification of epilepsy disease genes has provided valuable insight into disease mechanisms. However, few epilepsy genes are understood at a level that approaches a molecular understanding sufficient to help guide development of effective therapeutics, and thus far most successes are limited to channel proteins. Rapid expansion of human genome sequencing has identified new epilepsy genes of unknown function, and new approaches are needed to delineate their mechanisms of disease causality. A case in point is the human KCTD7 gene, a newly designated epilepsy/neurodegeneration gene. Mutations in KCTD7 cause progressive myoclonic epilepsy (EPM3), infantile onset neuronal ceroid lipofuscinosis (CLN14), and possibly other disorders. However, except for a growing number of reports identifying KCTD7 mutations in patients, essentially nothing is known about the molecular functions of KCTD7 (8 hits for KCTD7 in PubMed). Our goal is to uncover the underlying mechanisms of KCTD7 based on novel insights gained from our studies in yeast (Saccharomyces cerevisiae), combined with mammalian models of neuronal cell death, mitochondrial function and autophagy. A yeast genetic screen in our lab uncovered new functions for a yeast gene that has significant amino acid sequence similarity to the 24-member KCTD family of poorly characterized human proteins. KCTD7 is expressed specifically in neurons of the brain. Our studies in yeast suggest new unexpected functions for human KCTD7 in nutrient sensing and autophagy. We predict that the results of the proposed project will have a significant impact on the understanding of basic molecular mechanisms of KCTD7 as well as the mechanisms that underlie neurodegeneration and epilepsy in patients.
In Aim 1, we will use microscopy and biochemical approaches to establish the role of human KCTD7 in nutrient sensing and autophagy in cell lines and primary neurons.
In Aim 2, we will delineate mechanisms of KCTD7 activation and function, and in Aim 3 we will test the relevance of these molecular mechanisms by analyzing a new mouse model genetically engineered to mimic EPM3/CLN14 patients. We also expect to provide valuable insight into other neurodegenerative processes, and to advance the utility of mouse models in epilepsy research.
Approximately 1% of the US population has epilepsy with significant personal and economic impact. Available therapies fail to control seizures for almost a third of these individuals, and our limited understanding of the many different underlying mechanisms significantly impedes progress. We propose to translate unique findings from yeast to delineate the functions of a newly identified human disease gene that causes severe neurodegeneration and epilepsy in children.
|Chen, Xianghui; Wang, Guiqin; Zhang, Yu et al. (2018) Whi2 is a conserved negative regulator of TORC1 in response to low amino acids. PLoS Genet 14:e1007592|
|Aouacheria, Abdel; Cunningham, Kyle W; Hardwick, J Marie et al. (2018) Comment on ""Sterilizing immunity in the lung relies on targeting fungal apoptosis-like programmed cell death"". Science 360:|
|Hardwick, J Marie (2018) Do Fungi Undergo Apoptosis-Like Programmed Cell Death? MBio 9:|
|Metz, Kyle A; Teng, Xinchen; Coppens, Isabelle et al. (2018) KCTD7 deficiency defines a distinct neurodegenerative disorder with a conserved autophagy-lysosome defect. Ann Neurol 84:766-780|
|White, Kristin; Arama, Eli; Hardwick, J Marie (2017) Controlling caspase activity in life and death. PLoS Genet 13:e1006545|
|Tang, Ho Lam; Tang, Ho Man; Fung, Ming Chiu et al. (2016) In Vivo Biosensor Tracks Non-apoptotic Caspase Activity in Drosophila. J Vis Exp :|
|Tang, Ho Lam; Tang, Ho Man; Hardwick, J Marie et al. (2015) Strategies for tracking anastasis, a cell survival phenomenon that reverses apoptosis. J Vis Exp :|
|Tang, Ho Lam; Tang, Ho Man; Fung, Ming Chiu et al. (2015) In vivo CaspaseTracker biosensor system for detecting anastasis and non-apoptotic caspase activity. Sci Rep 5:9015|
|Teng, Xinchen; Hardwick, J Marie (2015) Cell death in genome evolution. Semin Cell Dev Biol 39:3-11|
|Hartman, Adam L; Santos, Polan; O'Riordan, Kenneth J et al. (2015) Potent anti-seizure effects of D-leucine. Neurobiol Dis 82:46-53|
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