Identification and analysis of Rab8 mutants: genetic enhancers of a Drosophila model of Frontotemporal Dementia

Frontotemporal dementia (FTD) is a progressive neurodegenerative disease associated with preferential atrophic degeneration of the frontal and temporal lobes of the brain. It is the second most prevalent early onset dementia, after Alzheimer’s disease, displaying an average age of onset between 45 and 65 years. FTD has a strong genetic association, with a positive familial history in approximately 50% of cases and autosomal dominance in up to 20%. One gene associated with the disease is Chromatin Modifying Protein 2B (CHMP2B). CHMP2B encodes a key component of Endosomal Sorting Complex Required for Transport III (ESCRT-III), which in turn is involved in the biogenesis of multivesicular bodies at the late endosome. Here we demonstrate Rab8 mutants dominantly enhance toxicity of the FTD CHMP2B mutation CHMP2BIntron5, when expressed in the Drosophila eye. Characterisation of neuronal morphology, at the larval neuromuscular junction, reveals Rab8 mutants display significant synaptic overgrowth, coupled with a reduction in synaptic bouton size. This abnormal morphology can be rescued by overexpressing wildtype Rab8 pre-synaptically, demonstrating a neuronal complement of Rab8 to be essential for normal synaptic growth. We also demonstrate that TGF-β signalling and JNK signalling, known regulators of synaptic assembly and function, are necessary for the unrestricted synaptic growth seen. Furthermore we identify the endosomal JNK scaffold POSH and the JNKKK TAK1 as a novel regulators of synaptic growth. Taken together these findings implicate Rab8 as a novel enhancer of CHMP2BIntron5 toxicity in a Drosophila model of FTD and as a potent regulator of synaptic growth. In addition they suggest a potential role for innate immune responses in the regulation of synaptic development.