PIKFYVE Modulation Mitigates TDP-43-Dependent Disease Phenotypes in a Drosophila Model of Amyotrophic Lateral Sclerosis

Abstract

Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease affecting both upper and lower motor neuron and marked by progressive muscle weakness. However, the pathogenic mechanisms underlying motor neuron death remain unclear. Currently there is no cure for ALS. Therapies fully capable of mitigating complex disease processes are not well developed and greatly needed. So far, three drugs Riluzole, Radicava and recently Terasemtiv, have been approved for ALS, but none of them are very effective. Recently, a small molecule modulator of vesicle trafficking (Apilimod) has been reported to rescue patients motor neuron survival and improve the degree of degeneration in mouse model of ALS based on C9ORF72 mutations. Here, I used a Drosophila model of ALS to test the therapeutic potential of Apilimod and its target, PIKFYVE, in TDP-43 proteinopathy. My results show that PIKFYVE knock down (PIKFYVE RNAi) in motor neurons rescue locomotor dysfunction caused by TDP-43. Consistent with the PIKFYVE knockdown results, Apilimod also rescues TDP-43-dependent locomotor dysfunction. PIKFYVE knockdown was also able to slightly improve lifespan in TDP-43 mutants. These findings confirm that PIKFYVE may provide a useful, albeit limited therapeutic target for TDP-43 proteinopathy.