My long-term objective is to develop and analyze invertebrate models to obtain a mechanistic understanding of hereditary human neurological diseases. The nematode Caenorhabditis elegans will be used for genetic analysis of loss-of-function diseases such as lissencephaly (LIS), and gain-of-function diseases, such as familial amyotrophic lateral sclerosis (FALS). Loss-of-function neurological diseases will be modeled by disrupting C. elegans disease gene homololues. Gain-of-function neurodegenerative disorders will be modeled by generating transgenic worms carrying gain-of-function disease transgenes. The powerful genetics of C. elegans will then be applied to analyze the molecular basis of neuronal cell death or dysfunction in these disorders. Suppressor and enhancer screens will be performed to identify novel genes that interact with loss-of-function disease gene homologues or gain-of-function disease transgenes, an approach not possible in transgenic mice. Such novel genes may not only provide insight into the molecular mechanisms of action of neurological disease genes, but may also constitute potential therapeutic targets. Genetic analysis of diverse aspects of C. elegans development has identified genes and pathways relevant to disease. Studies of apoptosis in C. elegans defined genes composing a programmed cell death pathway that is conserved in human. The creation of worm models of neurological diseases will provide an opportunity to study how upstream disease genes and downstream cell-death genes might interact. Because a large number of disease gene homologues have been identified in C. elegans, the project could in principal establish an approach with future applications to a wide range of neurological disorders.
|Hao, Limin; Ben-David, Oshrit; Babb, Suzann M et al. (2017) Clozapine Modulates Glucosylceramide, Clears Aggregated Proteins, and Enhances ATG8/LC3 in Caenorhabditis elegans. Neuropsychopharmacology 42:951-962|
|Hao, Limin; Buttner, Edgar A (2014) Methods for studying the mechanisms of action of antipsychotic drugs in Caenorhabditis elegans. J Vis Exp :e50864|
|Saur, Taixiang; DeMarco, Sarah E; Ortiz, Angelica et al. (2013) A genome-wide RNAi screen in Caenorhabditis elegans identifies the nicotinic acetylcholine receptor subunit ACR-7 as an antipsychotic drug target. PLoS Genet 9:e1003313|
|Karmacharya, Rakesh; Lynn, Spencer K; Demarco, Sarah et al. (2011) Behavioral effects of clozapine: involvement of trace amine pathways in C. elegans and M. musculus. Brain Res 1393:91-9|
|Karmacharya, Rakesh; Sliwoski, Gregory R; Lundy, Miriam Y et al. (2009) Clozapine interaction with phosphatidyl inositol 3-kinase (PI3K)/insulin-signaling pathway in Caenorhabditis elegans. Neuropsychopharmacology 34:1968-78|
|Buttner, Edgar A; Gil-Krzewska, Aleksandra J; Rajpurohit, Anandita K et al. (2007) Progression from mitotic catastrophe to germ cell death in Caenorhabditis elegans lis-1 mutants requires the spindle checkpoint. Dev Biol 305:397-410|