Academic journal article Genetics

The Mei-P26 Gene Encodes a RING Finger B-Box Coiled-Coil-NHL Protein That Regulates Seizure Susceptibility in Drosophilia

Academic journal article Genetics

The Mei-P26 Gene Encodes a RING Finger B-Box Coiled-Coil-NHL Protein That Regulates Seizure Susceptibility in Drosophilia

Article excerpt

ABSTRACT

Seizure-suppressor mutations provide unique insight into the genes and mechanisms involved in regulating nervous system excitability. Drosophila bang-sensitive (BS) mutants present a useful tool for identifying seizure suppressors since they are a well-characterized epilepsy model. Here we describe the isolation and characterization of a new Drosophila seizure-suppressor mutant that results from disruption of the meiotic gene mei-P26, which belongs to the RBCC-NHL family of proteins. The mei-P26 mutation reduces seizures in easily shocked (eas) and slamdance (sda) epileptic flies following mechanical stimulation and electroconvulsive shock. In addition, mutant mei-P26 flies exhibit seizure thresholds at least threefold greater than those of wild type. The mei-P26 phenotypes appear to result from missense mutation of a critical residue in the NHL protein-protein interaction domain of the protein. These results reveal a surprising role for mei-P26 outside of the germline as a regulator of seizure susceptibility, possibly by affecting synaptic development as a ubiquitin ligase.

HUMAN seizure disorders represent a serious health concern due to the large number of people affected as well as the inadequacy of available treatments. Seizures are defined as abnormal, synchronous, and rhythmic firing of neurons in the central nervous system. At least 10% of the population will experience a seizure during their lifetime and ^3% of people suffer persistent, spontaneous epileptic seizures (SHNEKER and FOUNTAIN 2003). This problem is amplified by the fact that one-third of epileptics cannot adequately control their seizures with medication (SHNEKER and FOUNTAIN 2003). Thus, seizure disorders represent a pervasive class of disease with unsatisfactory treatment options.

Seizures can result from a variety of brain insults including head trauma, fever, illness, and electroconvulsive shock, but a main source of seizure susceptibility appears to be genetic predisposition. More than 70 genes have been linked to epilepsy from work done on inherited disorders in humans, mice, and flies (NOEBELS 2003). These genes encode a wide variety of products ranging from ion channel proteins to tRNAs. The large number of disparate genes involved in epileptogeneis, as well as the frequent lack of obvious functional relationships between mutation and seizure susceptibility, complicates understanding epilepsy on a mechanistic level (JACOBS et al 2001).

Identification of genetic seizure suppressors is an underutilized resource for understanding seizures. Seizure suppressors are second-site modifier mutations that when combined with seizure-prone mutants are capable of reverting their seizure susceptibility to wild-type levels. Seizure-suppressor mutations are valuable for two main reasons: (1) they provide insight into the mechanisms underlying seizure susceptibility and (2) they provide potential targets for novel therapeutic drugs. By giving insight into seizure mechanisms, seizure suppressors can reveal new relationships and novel roles for genes in the nervous system.

One organism that avails itself to seizure-suppressor screening is Drosophila. The fly has well-characterized genetics, behavior, and electrophysiology and is amenable to high-throughput mutagenesis screens. In addition, a Drosophila model of epilepsy exists in the bang-sensitive (BS) class of behavioral mutants. The BS mutants are so named because they exhibit increased susceptibility to seizures following mechanical stimulation and electroconvulsive shock. The BS mutant class includes among others bangsenseless (bss; gene unknown), easily shocked (eas; ethanolamine kinase gene), and slamdance (sda; aminopeptidase gene). BS mutants are well characterized on a behavioral and electrophysiological level and their seizure activity shows numerous similarities with seizure activity in humans, making them a useful tool for identifying new seizure suppressors (BENZER 1971; KUEBLER and TANOUYE 2000; HEKMAT-SCAFE et al 2005). …

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