Interaction of Rab8 with OCRL1: Synaptic growth function in Frontotemporal Dementia and the Neurodevelopmental Disorder Lowe Syndrome

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Frontotemporal dementia (FTD) causes a devastating dementia that strikes around 55-65years of age. This disease accounts for a significant percentage of pre-senile dementias and is a considerable burden on society, in terms of care and costs. In a search for genes that drive the progression of the disease, we found two genes, Rab8 and OCRL1. These genes have been proposed to act together, though the reason and purpose is not known. The OCRL1 gene is known to be dysfunctional in another disease known as Lowe Syndrome (LS). Mutations in OCRL1 lead to cataracts, kidney dysfunction and impaired mental function. This makes our study of fundamental importance to our understanding of both FTD and LS. Until now, study of both of these genes has been difficult in other genetic systems (mouse and zebrafish) due to genes with closely related function being present in the animals and causing redundancy. We are using Drosophila, the fruit fly, because of the advanced genetics that we can use with this organism and because it has a functioning nervous system that we can readily study. We have made mutants in the fly versions of OCRL1 and Rab8 and these mutants have interesting neurological defects. Using our mutants, we can study the function of OCRL1 (important for understanding LS) and the function of Rab8 in the nervous system and this will inform us of events occurring in neurons of FTD affected individuals. We can also use these mutants to understand how the two genes interact, furthering our understanding of FTD. Our labs in Manchester and York are in touch with the Alzheimer's Society and the Lowe Syndrome Trust where we communicate our work. We also interact with schools and run practical classes to demonstrate how fun and effective our experiments can be. Our study is therefore critical to our understanding of two important diseases affecting our society, FTD and LS.