Dr Sean Sweeney
University of York
Dissecting the cellular mechanisms driving disease progression in CHMP2B activated Frontotemporal Dementia: Identifying Innate immune activation and the co-regulation of membrane traffic in neurons
Frontotemporal Dementia (FTD) is the most common pre-senile dementia after Alzheimer’s Disease with an onset in the fourth or fifth decade. FTD has a strong genetic component mutations in seven different genes have been identified that cause the disease. Our understanding of the molecular steps driving disease progression is at a very early stage. To advance this area of research we have employed the rapid and powerful system of Drosophila genetics, a tool critical in recent advances in our understanding of Alzheimer’s Disease and Parkinson’s disease, in addition to identifying potential therapeutic drugs for these conditions. We have developed a model of FTD in Drosophila and used this in a genetic screen to identify phenotypic enhancing and suppressing mutations. Our screen identifies components of autophagy and innate immunity acting in the neuron affected by the FTD mutation. One loci we have identified is Rab8. Examining synapses of Rab8 reveals that Rab8 is a regulator of synapse growth responses. Further examination shows that these growth responses are downstream of an innate immune response. We wish to examine the source and pathway of the innate immune response as it affects synapse growth and autophagy, a juncture in cell regulation that appears to be under control of rab8 and therefore of critical importance to FTD dysfunction. We will use our Drosophila data to test a mouse FTD model for similar responses. A number of existing pharmaceuticals are known to regulate the innate immune response. Our work therefore suggests a point of therapeutic intervention.