Abstract
TDP-43 is an evolutionarily conserved RNA binding protein recently associated with the pathogenesis of different neurological diseases. At the moment, neither its physiological role in vivo nor the mechanisms that may lead to neurodegeneration are well known. Previously, we have shown that TDP-43 mutant flies presented locomotive alterations and structural defects at the neuromuscular junctions. We have now investigated the functional mechanism leading to these phenotypes by screening several factors known to be important for synaptic growth or bouton formation. As a result we found that alterations in the organization of synaptic microtubules correlate with reduced protein levels in the microtubule associated protein futsch/MAP1B. Moreover, we observed that TDP-43 physically interacts with futsch mRNA and that its RNA binding capacity is required to prevent futsch down regulation and synaptic defects.
Highlights
TDP-43 is an RNA binding protein of 43 kDa that belongs to the hnRNP family and plays numerous roles in mRNA metabolism such us transcription, pre-mRNA splicing, mRNA stability, microRNA biogenesis, transport and translation [1,2]
Muscle development was normal in TBPH mutant flies since no differences in organ growth, cytoskeleton organization or postsynaptic differentiation were observed regarding to wild type controls (Figure S1A–F and G)
Concluding remarks In this work, we show that in our TBPH minus Drosophila model the changes observed at the level of neuromuscular junctions (NMJs) and synaptic boutons formation can be explained by defects at the cytoskeleton level, which in turn are mediated by a down regulation of the futsch protein
Summary
TDP-43 is an RNA binding protein of 43 kDa that belongs to the hnRNP family and plays numerous roles in mRNA metabolism such us transcription, pre-mRNA splicing, mRNA stability, microRNA biogenesis, transport and translation [1,2]. TDP-43 is very well conserved during the evolution, especially with regards to the two RNA-recognition motifs (RRMs), the first (RRM1) being responsible for the binding of TDP-43 with UG rich RNA [3] In consonance with these described functions, TDP-43 prevalently resides in the cell nucleus where it co-localizes with other members of the RNA processing machinery [4]. It should be noted that overexpression of TDP-43 in Drosophila has been reported to increase dendritic branching [9], lead to motor dysfunction and reduced life span [10], axon loss and neuronal death [11], is generally toxic regardless of inclusion formations [12], and at least in part is the cause behind the degeneration associated with TER94 mutations which is the Drosophila homologue of the VCP protein [13]. In consideration that Drosophila TDP-43 (TBPH) can functionally substitute for human TDP-43 in functional splicing assays [14], all these reports confirm that Drosophila may represent a highly suitable animal model to investigate TDP-43 functions both in normal and disease conditions
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