Epilepsy is an important human disease because it causes physical trauma and sudden death in addition to immense social and economic hardship. The genetic basis of a number of epilepsy syndromes has been identified but the precise mechanism whereby mutations produce seizures is unknown. Several mutations in the alpha4 neuronal nicotinic receptor (a4 nAChR) gene have been identified in Autosomal Dominant Nocturnal Frontal Lobe Epilepsy (ADNFLE). This is a rare form of inherited epilepsy character ....Epilepsy is an important human disease because it causes physical trauma and sudden death in addition to immense social and economic hardship. The genetic basis of a number of epilepsy syndromes has been identified but the precise mechanism whereby mutations produce seizures is unknown. Several mutations in the alpha4 neuronal nicotinic receptor (a4 nAChR) gene have been identified in Autosomal Dominant Nocturnal Frontal Lobe Epilepsy (ADNFLE). This is a rare form of inherited epilepsy characterized by the presence of seizures during light sleep. In vitro studies using the human mutated DNA (i.e. DNA containing the genetic defect) have suggested that this mutation results in reduced activity of the receptor. Therefore a mouse in which this gene is destroyed would be relevant in understanding the human disease. We have generated an a4 nAChR knockout (KO) mouse and plan to use the mouse to test the idea that loss of function of the a4 nAChR in vivo is associated with enhanced seizure activity. The KO mice do not have unprovoked seizures but appear to have an increased number of major motor seizures in response to pentylenetetrazole, an agent which is known to cause seizures by blocking the effects of the brain inhibitory molecule GABA. Interestingly, a4 nAChRs are known to control the release of GABA. We therefore propose that our knockout mice have seizures because they tend to under produce GABA. We will also make and analyse a mouse line with the same genetic mutation as patients with ADNFLE. The experiments are aimed at understanding the way that seizures are generated and spread in the brain in these rare forms of epilepsy. The hope is that understanding these mechanisms will help us better understand and therefore treat common forms of epilepsy.Read moreRead less
The body tightly controls when and where proteins are made. Likewise once a protein has performed its function, it must be removed. Targeted proteolysis serves to reset the cell so that it can respond anew to stimuli that trigger growth and cell development. The Siah proteins are a family of proteins that control the turnover of other proteins. Siah proteins are remarkably highly conserved in evolution, and counterparts of the human proteins can be found in fruitflies, worms and plants. There ar ....The body tightly controls when and where proteins are made. Likewise once a protein has performed its function, it must be removed. Targeted proteolysis serves to reset the cell so that it can respond anew to stimuli that trigger growth and cell development. The Siah proteins are a family of proteins that control the turnover of other proteins. Siah proteins are remarkably highly conserved in evolution, and counterparts of the human proteins can be found in fruitflies, worms and plants. There are three different types of Siah protein in mice and this study investigates the function of the each protein by creating mice that lack one or more of these proteins. Our work to date has revealed that the Siah genes are involved in growth and fertility of mammals. The genes are also important for cell division, which implicates them in proliferative diseases such as cancer.Read moreRead less