Fos regulates age-dependent neuroinflammation in a <i>VAPP58S</i> model of amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive loss of motor function. Here, we developed a Drosophila model of ALS8 (VAPBP58S) using CRISPR/Cas9 genome editing. VAPB is an endoplasmic reticulum-based adapter protein associated with and regulating intracellular membrane:membrane contact sites. VAPBP58S flies showed progressive age-dependent motor deficits and a shortened lifespan, paralleling features of the human disease. VAPBP58S brains exhibited age-dependent neuroinflammation, as measured by whole-transcriptome quantitative mRNA sequencing, suggesting a broad, low-grade enhancement of signalling across multiple immune pathways (Toll, Imd, Jak-STAT and c-Jun). Our results indicated that glial cells in the brain are the site of brain inflammation and identified the Drosophila orthologue of Fos (Kayak) as a key modulator of age-dependent inflammation. In accordance, we found that overexpression of wild-type kayak or its dominant-active variant kayakK357R in glia reduced inflammation and, concomitantly, improved motor function. In contrast, knockdown of glial kayak accelerated age-dependent deterioration of motor function and enhanced neuroinflammation. Our study underscores the roles of glial-modulated brain inflammation in dictating ALS8 progression and identifies kayak as a central negative regulator of neuroinflammation in disease.