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bioRxiv · 10.64898/2026.02.28.708780

Fos regulates age-dependent neuroinflammation in VAPBALS

Kulkarni, N. P.·Thulasidharan, A.·Soory, A.·Goel, P.·Kelkar, V.·RATNAPARKHI, G. S.
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Abstract

Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive loss of motor function. We have developed a Drosophila model of ALS8 (VAPBP58S) using CRISPR/Cas9 genome editing. VAPB is an ER-based adapter protein associated with and regulating intracellular membrane:membrane contact sites. VAPBP58S flies show progressive age-dependent motor deficits and a shortened lifespan, paralleling features of the human disease. VAPBP58S brains exhibit age-dependent neuroinflammation, as measured by whole-transcriptome quantitative mRNA sequencing, suggesting a broad, low-grade enhancement in signalling in multiple (Toll, IMD, Jak-STAT and Jun-kinase) immune pathways. We implicate glial cells in the brain as the site of brain inflammation and identify Drosophila Fos (Kayak) as a key modulator of age-dependent inflammation. In accordance, we find that overexpression of wild-type kayak or its dominant-active variant kayakK357R in glia reduces inflammation and, concomitantly, improves motor function. In contrast, knockdown of glial kayak accelerates age-dependent deterioration of motor function and enhances 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. Summary StatementWe uncover definitive evidence for age-dependent neuroinflammation, originating from glial cells and regulated by Fos, as a key mechanism underlying Amyotrophic Lateral Sclerosis 8.

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Kulkarni, N. P., Thulasidharan, A., Soory, A., Goel, P., Kelkar, V., RATNAPARKHI, G. S.. 2026-03-03. Fos regulates age-dependent neuroinflammation in VAPBALS. https://doi.org/10.64898/2026.02.28.708780

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