The Role of Muscular TDP-43 in Neuromuscular Junction Development and Progress of ALS

Strah, Nina (2019). The Role of Muscular TDP-43 in Neuromuscular Junction Development and Progress of ALS. PhD thesis The Open University.



Amyotrophic lateral sclerosis (ALS) is a fatal disease with fast progression. Patients usually die three to five years after diagnosis. The main characteristics are progressive neurodegeneration, following muscular weakness, and atrophy. The most common cause of death is respiratory muscle failure. Studies have shown that the highlight of the disease is TDP-43 inclusions in neuronal cytoplasm. The symptoms of ALS can be recapitulated in Drosophila melanogaster. The Drosophila‘s ortholog is called TBPH. TBPH knockout flies show locomotion problems, shorter lifespan, and anatomical changes in the neuromuscular junction (NMJ).

Our studies aimed to reveal the function of TBPH in muscles. We took advantage of RNA interference and silenced the protein exclusively in muscles. Moreover, we expressed TBPH in tbphΔ23/- fly and tried to understand whether it can rescue reduced mobility, lifespan, and anatomical properties of NMJ. We observed changes in lifespan, motility, and NMJ structure when TBPH was silenced in muscles. Expression of the protein in tbphΔ23/- Drosophila completely recovered the motility of larvae and the level of proteins located in the postsynaptic compartment of NMJ. One of the proteins was Disc large (Dlg), known as scaffold protein involved in NMJ development and maintenance of NMJ structure. Expression of Dlg recovered the phenotype in terms of mobility, lifespan, and NMJ formation. We also demonstrated that the drop of Dlg levels could be seen in neuroblastoma cells and differentiated iPS cells of ALS patients. With that been discovered, not only have we confirmed the relevance of our studies, but we have also opened a new possibility for drug development and treatment. Moreover, with the research, we contributed to a recent hypothesis that muscles can be involved in the onset of ALS.

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