RNA helicase maheshvara interacts with TDP-43 and exacerbates neurodegeneration in Drosophila model of amyotrophic lateral sclerosis

Abstract

Drosophila maheshvara (mahe) encodes a conserved DEAD box RNA helicase that regulates various important signaling pathways like Notch and JAK/STAT, pathways that have been functionally implicated in neuronal development. In order to identify novel modulators of mahe as well as to unravel its role in neurodegenerative disorders, a genetic modifier screen using Drosophila models of neurodegenerative disorders was carried out. From this screen, we identified mahe to be a potent modifier of TDP-43 mediated proteinopathy in Drosophila model of Amyotrophic Lateral Sclerosis (ALS). We demonstrate that Mahe genetically interacts and associates with cytosolic hyperphosphorylated toxic aggregates of TDP-43 leading to enhanced TDP-43 mediated neurodegenerative phenotype. Increased autophagy, cytoskeletal disruption, and FMRP-mediated translational repression of neuronal target Futsch were observed, potentially contributing to neuronal dysfunction. The current study indicates a strong interaction of mahe and TDP-43 (TARDBP) resulting in augmentation of TDP-43 mediated neurodegenerative phenotypes which parallels ALS clinical pathology. © 2025