The effect of ALS-linked gene disruption in motor neurons

Abstract

Amyotrophic Lateral Sclerosis (ALS) is a late onset, neurodegenerative condition characterized by degeneration of upper and lower motor neurons and scarring of the lateral spinal cord. Throughout the years, mutations in several genes were identified and found to contribute to the onset of this condition, the most common ones being variations in SOD1, C9orf72, TARDBP and FUS. The variants of these genes have been extensively studied to understand the mechanisms by which they cause ALS. Different studies support both loss and gain of function mechanisms as possible ways by which these variants cause ALS, however further in-depth studies are warranted. Using Drosophila melanogaster as an animal model, and the GAL4-UAS system of gene expression, various ALS-linked transgenic variants were selectively overexpressed in the motor neurons of these organisms using the three different motor neuron drivers, OK6-GAL4, D42-GAL4 and OK371-GAL4. Most of the transgene variants tested including hTDP-43CTF, TBPH, hFUSWT-RFP-HA, hFUSP525L-RFP-HA and 100-hexanucleotide glycine-arginine repeats in C9orf72 consistently resulted in decreased larval mobility when they were expressed using all three drivers. The effect of overexpression of HA-FUSWT and C9orf72-associated 100-hexanucleotide proline-arginine repeats on larval mobility varied depending on which GAL4 driver was used. Adult viability, however, was negatively affected upon overexpression of all ALS-related transgenes in motor neurons. Additionally, out of the three drivers used, the glutamatergic motor neuron specific OK371-GAL4 driver, caused the most consistent negative effects on larval mobility and adult fly viability, highlighting the significance of these neurons in disease pathogenesis. These results emphasize the importance of TARDBP, FUS and C9orf72 genes in ALS-associated motor neuron degeneration and paves the way for further research on the pathogenic mechanisms of damaging variants in these genes which can be targeted by potential future treatments.