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

额颞性痴呆(FTD)会导致一种毁灭性的痴呆症，发病年龄在55-65岁之间。这种疾病占老年前痴呆的很大比例，在护理和费用方面对社会造成相当大的负担。在寻找推动疾病进展的基因时，我们发现了两个基因，Rab8和OCRL1。这些基因被认为是共同作用的，尽管原因和目的尚不清楚。众所周知，OCRL1基因在另一种名为洛威综合征(LS)的疾病中功能失调。OCRL1基因突变会导致白内障、肾功能障碍和精神功能受损。这使得我们的研究对我们理解FTD和LS都具有重要的意义。到目前为止，在其他遗传系统(老鼠和斑马鱼)中对这两个基因的研究一直很困难，因为动物中存在与功能密切相关的基因，并导致冗余。我们正在使用果蝇，因为我们可以对这种生物使用先进的遗传学，因为它有一个我们可以很容易研究的正常运作的神经系统。我们已经在苍蝇版本的OCRL1和Rab8中进行了突变，这些突变具有有趣的神经缺陷。使用我们的突变体，我们可以研究OCRL1(对理解LS很重要)和Rab8在神经系统中的功能，这将使我们了解FTD患者神经元中发生的事件。我们还可以利用这些突变体来了解这两个基因是如何相互作用的，从而进一步了解FTD。我们在曼彻斯特和约克的实验室与阿尔茨海默氏症协会和洛威综合症信托基金保持联系，我们在那里交流我们的工作。我们还与学校互动，开设实践课，展示我们的实验是多么有趣和有效。因此，我们的研究对于我们理解影响我们社会的两种重要疾病FTD和LS至关重要。

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.