Neuro-glial lipid imbalance in a Drosophila model of amyotrophic lateral sclerosis 8.

Overview

1. Department of Biology, Indian Institute of Science Education and Research (IISER), Dr Homi Bhabha Road, Pashan, Pune, 411008 India
2. Biotechnology Research and Innovation Council - National Centre for Cell Science (BRIC-NCCS), Savitribai Phule Pune University Campus, Ganeshkhind Road, Pune, 411007 India

Abstract

Membrane Contact sites (MCS) have emerged as physiologically relevant zones that coordinate inter-organelle communication and cellular function. VAPB, an ER-resident MCS tethering protein, plays a central role in regulating MCSs through its numerous protein interactors, thereby influencing cellular homeostasis. A pathogenic missense VAPBP56S mutation causes familial Amyotrophic Lateral Sclerosis 8 (ALS8) in humans, with progressive degeneration of motor neurons. The precise mechanisms underlying the motor neurodegeneration remain poorly understood. In this study, we examine lipid imbalance in the brain of a Drosophila model of ALS8 (VAPBP58S). Specifically, we find that lipid homeostasis is disrupted in an age-dependent manner. Strikingly, cholesterol esters and sphingolipids show an age-dependent increase, while cholesterol shows a decrease. Intriguingly, from a cellular perspective, despite the accumulation of triacylglycerols (TAGs) in the brains of VAPBP58S animals, the increased neutral lipid species do not correlate with lipid droplets (LDs), which are fewer in density and smaller in size. Lipid imbalance and progressive motor dysfunction in VAPBP58S animals can be reversed by expressing VAPBWT, suggesting a relationship between VAPB activity and lipid flux. To uncover VAPB’s role in lipid homeostasis, we modulate VAPB activity in neurons and glia to dissect out tissue-specific roles. We find that both cell types contribute to lipid homeostasis in differential ways. In glia, LD flux is strongly dependent on VAPB activity, a dependence further recapitulated in cultured human cell lines, suggesting evolutionary conservation of the regulatory mechanism. Thus, we hypothesize that lipid dysregulation constitutes a critical pathogenic feature of ALS8, with the VAPBP56S allele disrupting lipid homeostasis in the neuro-glial axis.

Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1186/s40478-026-02391-y.

Reproduced under the paper's license (CC BY), from the paper cited above.

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All data supporting the findings of this study are available within the paper and its Supplementary Information.

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Version 1, 27 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 7 authors, 6 keywords, 11 MeSH terms, 3 funders, 111 references.

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This paper

Garg, L., Chaplot, K., Kuppili, G., Tendulkar, S., Joseph, J., Kamat, S., & Ratnaparkhi, G. (2026). Neuro-glial lipid imbalance in a Drosophila model of amyotrophic lateral sclerosis 8. Acta neuropathologica communications, 14(1), 189. https://doi.org/10.1186/s40478-026-02391-y

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