Frontotemporal Dementia (FTD) and Amyotrophic Lateral Sclerosis (ALS) are two overlapping neurodegenerative disorders characterised by the dysfunction and the death of neurons. They are considered two ends of a spectrum that share common pathological mechanisms. Different mutations in several human genes, involved in endosomal traffic and RNA regulation, can cause FTD, ALS or both. Mutations in charged multivesicular body protein 2B (CHMP2B), whose main known function is endolysosomal cargo trafficking and biogenesis of multivesicular bodies (MVB), can cause FTD and ALS. In this thesis, the mutation of interest is a G>C transition in the splice acceptor site of exon 6 resulting in a toxic variant, CHMP2BIntron5, where the C-terminal of the protein is truncated. This specific mutation causes a rare hereditary form of FTD, FTD-3. This work establishes a role for Drosophila CHMP2B (dCHMP2B) at the synapse, demonstrating a neuronal functional requirement.
Pathologically, the majority of ALS cases have TDP-43 aggregation, whereas FTD cases have inclusions that are either tau or TDP-43 positive. FTD-3 has no apparent inclusions. Despite the lack of TDP-43 pathology, this thesis identifies a genetic interaction between CHMP2B and TDP-43, and interacting-TDP-43 pathways, in health and disease of the Drosophila nervous system. TDP-43 functions as an RNA regulatory protein that binds to small RNAs. In this investigation, two RNA regulatory pathways are identified as modifiers of the toxicity caused by CHMP2BIntron5 expression in our Drosophila model: retrotransposon/retrovirus (RT/RV) reactivation and nonsense-mediated decay (NMD) dysregulation. Taken together, these findings reinforce the idea that RNA dysregulation and endosomal dysfunction are two cellular mechanisms that converge under the pathology of FTD/ALS.
