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Gbadamosi, Monsurat Titi
(2021).
DOI: https://doi.org/10.21954/ou.ro.0001322c
Abstract
The most abundant pathological protein in the debilitating neurodegenerative disease, Amyotrophic Lateral Sclerosis (ALS) is TDP-43. Knock-down of its Drosophila homologue TBPH, recapitulates the disease in fly, with mutants showing reduced life span and locomotion impairment among other features. These can be restored by expressing human TDP-43 both in neurons and glial cells. It has been observed in TBPH mutants a reduction of the Futsch protein, the homologue of the human MAP1B responsible for the stabilization of the synaptic microtubule cytoskeleton during growth at the neuromuscular junction. We used our Drosophila model of ALS to investigate the role of Futsch in the rescue of locomotion defects observed in the disease using the UAS-GAL4 system. Futsch expression in TBPH mutants using both pan-neuronal and motor neuron-specific drivers show a significant rescue of larval motility. The synaptic organization defect observed in the mutants was recovered through the restoration of the synaptic branches, boutons and shape. Also some synaptic and vesicle proteins such as Dlg, Synapsin, Syntaxin, Csp and acetylated tubulin were recovered. The defect in the cycling of synaptic vesicles and the level of the BMP signal transducer, pMad were ameliorated by the expression of Futsch in TBPH mutants. It is interesting to note that TBPH mutants expressing the 4 GTPases Rab4 and Rab5, which are vesicle proteins associated with endosomal trafficking and recycling, were able to recover the levels of Futsch, acetylated tubulin and synaptic pMad. However, only Rab4 gave also a functional recovery of improved locomotion despite its reduced expression level compared to Rab5. We conclude that improved synaptic vesicle recycling system and enhanced BMP growth signalling are parts of the mechanisms involved in the recovery of locomotion defects observed in TBPH mutants expressing Futsch. We speculate that this recovery may be achieved through the functional anatomical recovery of the synaptic organization at the neuromuscular junction via the enhanced BMP growth signalling. Also included in the speculation is improved neurotransmission at the synaptic terminals resulting from the recovered vesicle recycling system.
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CORE (COnnecting REpositories)
