MODELING ATP13A2-DRIVEN NEURODEGENERATION IN ZEBRAFISH

ATP13A2 is a member of the P5B subfamily of P-type ATPases. Loss-of-function mutations in ATP13A2 are implicated in a spectrum of neurodegenerative disorders, including a complicated form of hereditary spastic paraplegia (SPG78), Kufor–Rakeb syndrome, Amyotrophic Lateral Sclerosis, and Neuronal Ceroid Lipofuscinosis. The protein is predominantly expressed in dopaminergic neurons, where it localizes to the endolysosomal compartment and plays a critical role in maintaining cytoplasmic polyamine homeostasis and lysosomal pH. Despite its importance, the pathophysiological mechanisms underlying ATP13A2 dysfunction remain incompletely understood.Across multiple ATP13A2-deficient animal models, widespread reactive gliosis—particularly astrogliosis—is frequently reported, even though ATP13A2 is expressed at relatively low levels in astrocytes and its specific function in glial cells remains poorly defined. We hypothesize that targeting astrogliosis in combination with restoring lysosomal function may beneficially modulate disease progression in ATP13A2-related disorders. However, testing this hypothesis requires a model that both recapitulates key pathological features and is well suited for drug discovery.The aim of this study is to investigate ATP13A2-linked neurodegeneration in vivo using multiple zebrafish models: a commercially available, previously published ENU-mutagenized line and a novel, up-to-date line generated by CRISPR–Cas9–mediated mutagenesis. Our analyses focus primarily on motor impairment and astrogliosis. Ultimately, we aim to further characterize astrocyte-specific signatures by combining transgenic zebrafish lines with omics approaches to dissect the contribution of astrocytes to ATP13A2-associated neurodegeneration and to identify potential therapeutic targets.