Surface glia predominantly contribute to the development of ALS/FTD in Drosophila model

Abstract

Backgrounds Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disorder characterized by motor neuron degeneration in the primary motor neurons. C9orf72 repeat expansion mutation is the most prevalent genetic causes of ALS/FTD. Due to the complexity of ALS, there has been no successful therapy for the condition. The traditional neurocentric concept of ALS derives in part from the assumption that the degradation of motor neuron (MN) cells in ALS is driven by cell-autonomous mechanisms, however, recent research has focused on the non-cell-autonomous pathogenic mechanisms such as glial, immune cells and blood-brain barriers participate in the degeneration of MNs in ALS. Drosophila melanogaster is widely used as a genetic model for ALS, giving essential mechanistic data on disease onset and development. Methods Using newly developed genetic tools to individually mark each subtype of the adult glial system in the fruit fly, we demonstrate that surface glia is the major and the only glial subtypes for the pathogenesis of C9orf72-mediated ALS/FTD. Results The surface glia of flies is the most critical of the six different subtypes of fly glia when it comes to developmental toxicity as well as anomalies in adult locomotion and lifespan. The fact that the expression of DPR in surface glia did not result in the death of neurons or glia in the CNS (Fig. 10) lends credence to the hypothesis that C9orf72-mediated defects in adult physiology are not caused by deficiencies only in the CNS. Conclusion Therefore, understanding the non-cell autonomous pathogenic pathways in ALS requires an understanding of surface glia.

Glia‐specific expression of neuropeptide receptor Lgr4 regulates development and adult physiology in Drosophila

“…Each dot represents 50 animals. See Section 2 and previous report Snow et al., 2022 for detailed quantification methods of climbing assay and mating assay. (c and d) Bar graphs with dot plots represent the percent of male flies successfully mated within 1 h with wild‐type virgin female.…”

“…We evaluated the lethality of various RNAi strains expressed by tissue‐specific GAL4s using two separate methods (Snow et al., 2022). First, to measure the effects of each cross for lethality, we used TM3 or TM6B balancer chromosomes.…”