Seizing the Role of Vesicle Targeting in Epilepsy Via CarpeDB and Roundworms

Genes throughout development govern synaptic transmission and, thus, neuronal excitability in both roundworms and humans. Notably, malfunction of synaptic vesicle targeting through the absence of essential regulatory proteins often leads to neurological dysfunction. Experimental results from our laboratory demonstrate that mutations or RNA interference (RNAi) against synaptic vesicle targeting proteins DHC-1 (dynein heavy chain), LIS-1, SNB-1 (synaptobrevin), and UNC-104 (kinesin) greatly increase a susceptibility to epileptic-like convulsions in the roundworm, C. elegans, by disrupting neurotransmission of GABA, the principal inhibitory transmitter of the central nervous system. Using bioinformation from our comprehensive database on epilepsy genetics, CarpeDB, and RNAi-mediated convulsion analysis with an antagonist of GABAergic reception, pentylenetetrazole (PTZ), we have accelerated the characterization of C. elegans synaptic vesicle targeting proteins that share significant human homologies (e.g. cytoskeletal motors, rabs, and SNAREs). These results help establish C. elegans as a model system for discovering new genes with implications for epilepsy. Introduction Epilepsy ranks as the third most common neurological disorder, affecting fifty million people worldwide, and is characterized by paroxysmal electrical disturbances of the brain that are manifested as seizures. Epilepsy is often etiologically classified into two major categories: symptomatic and idiopathic. Symptomatic epilepsy is of known cause and is often typified by damage to the central nervous system. Conversely, idiopathic epilepsy lacks an identifiable cause and is believed to result from both environmental and, most notably, genetic factors (1). Thus far, much research into the molecular basis of epilepsy, as well as closely related disorders like Alzheimer’s disease, dystonia, lissencephaly, and tuberous sclerosis, has led to the identification of numerous genes implicated in this disorder. For example, gene products such as ion channels, molecular chaperones, synaptic vesicle components, and transcription factors have been shown to influence seizure susceptibility. However, despite countless hours of research, scores of “epilepsy genes” have not yet been isolated (2, 3). Much of the difficulty surrounding the identification and characterization of epilepsy genes is intimately associated with prevalent experimental methods. That is, most epilepsy researchers have chosen to limit their studies to mammalian organisms, such as Mus musculus (the mouse) and Rattus norvegicus (the rat), which exemplify nervous system complexities quite similar to those of humans. Unfortunately, this complexity substantially hinders screening for epilepsy genes, as it necessitates costly and inefficient procedures (3). Quite possibly, an absence of sufficient data compilation has also impeded the search for novel genetic factors influencing susceptibility to epilepsy. Although multiple Web-based resources, such as NCBI, the Gene Ontology Consortium, the Human Gene Mutation Database (HGMD), Pfam, Uniprot, FlyBase, Mouse Genome Informatics, Rat Genome Database, and Wormbase offer valuable information that may be applied toward epilepsy genetics, those sites frequently truncate their information and disallow routine submission of nascent data from users. Furthermore, none of the aforementioned resources is comprehensive with each resource containing only fragments of pertinent information on specific genes and their epileptic roles. Consequently, these resources are recalcitrant to the specificity and autonomy for data submission or retrieval ideally desired for the acceleration of epilepsy research. Accordingly, we have utilized the aforementioned resources to establish a publicly accessible, dynamic Web site on epilepsy genetics.