Abstract:
Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disorder marked by progressive loss of motor function. It is a multigenic disease with complex pathophysiology, diverse clinical manifestations and multifactorial cellular dysfunctions, making it one of the most challenging neurodegenerative disorders to treat. Among the many ALS-associated genetic loci, our lab focuses on the eighth locus, vesicle-associated membrane protein-associated protein B (VAPB/ALS8). Multiple mutations in VAPB have been implicated in ALS8 in humans, the most studied being a Proline-to-Serine (VAPBP56S) point mutation. We developed an equivalent Drosophila mutant (VAPP58S) using CRISPR/Cas9 gene editing to model the disease in flies. VAPP58S flies showed progressive age-dependent motor deficits and a shortened lifespan (approximately 50% of wild-type). Whole-transcriptome mRNA sequencing of adult VAPP58S brains further revealed increased age-dependent inflammation. Through a glial enhancer-suppressor screen, we identified the Janus Kinase (JNK) pathway transcription factor, kayak (dFos), as a novel modulator of inflammation in the VAPP58S flies. Glial overexpression of kayak reduces inflammation and significantly improves motor function, whereas glial knockdown of kayak exacerbates inflammatory responses and accelerates age-dependent motor decline. Similarly, overexpression of a dominant-active kayak variant (kayakK357R) in glia ameliorates inflammation and motor dysfunction in the VAPP58S flies. Together, our findings highlight the critical role of glia-mediated inflammation in shaping ALS8 progression and establish kayak as a key regulator of inflammatory signalling in disease.
