TDP-43 Regulates Drosophila Neuromuscular Junctions Growth by Modulating Futsch/MAP1B Levels and Synaptic Microtubules Organization

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.

Partial loss of TDP-43 function causes phenotypes of amyotrophic lateral sclerosis

“…Loss-of-function models in invertebrates and zebrafish have shown a wide range of defects, ranging from embryonic lethality to morphological and functional defects of the nervous system, vascular system, and muscle degeneration (27,31,(34)(35)(36)(37). In mammalian species, TDP-43 gene deletion leads to early embryonic lethality (38)(39)(40)(41).…”

Sonic Hedgehog and TDP-43 Participate in the Spontaneous Locomotor Recovery in a Mouse Model of Spinal Motoneuron Disease

“…This finding is novel and promising for a couple of reasons: for instance, it has been recently found that TDP-43 modulates the local translation of mRNAs at the synapse, thus participating in a complex regulation of synaptic strength [30,31]. Moreover, other recent findings have proven that the depletion of TDP-43 could cause locomotor deficits in Drosophila by affecting the synaptic function [28,32]. Interestingly, Shh seems to impact on synaptic plasticity by similar mechanisms, including the modification of the presynaptic terminal size, synaptic vesicle size, and postsynaptic currents [10,19,20,44].…”

“…For instance, it has been found that TDP-43 could be localized in the synapses, likely affecting the local RNA translation and acting as a neuronal activity-responsive factor [30,31]. Interestingly, TDP-43 could also have a role in the motoneuron synaptic function and plasticity [28,[32][33][34].…”

Emerging Roles for hnRNPs in post-transcriptional regulation: what can we learn from flies?

“…Indeed, flies mutants for TBPH closely reproduce most of the phenotypes observed in ALS patients like decreasing viability, affected synaptic transmission, defective locomotion and also age-related progressive neurodegeneration (Ritson et al 2010;Hazelett et al 2012;Li et al 2010;Neumann et al 2006). Recently, it has emerged that TBPH interacts with the Futsch protein, the Drosophila homolog to human MAP1B (Godena et al 2011) (Fig. 4d).…”

“…4d). A reduced interaction between TBPH and Futsch seems to be responsible for the alteration in the organization of synaptic microtubules (Godena et al 2011).…”