EXPLORING NEUROINFLAMMATORY AND MICROGLIAL DYSFUNCTIONS IN ARSACS WITH A MULTI-MODEL APPROACH

Autosomal Recessive Spastic Ataxia of Charlevoix–Saguenay (ARSACS) is a rare neurodegenerative disorder caused by mutations in the SACS gene, which encodes sacsin, a multifunctional protein involved in protein quality control, mitochondrial homeostasis, and cytoskeletal regulation. While ARSACS has traditionally been considered a neuron-centric disease, recent evidence indicates high sacsin expression in astrocytes and microglia, suggesting that glial dysfunction and neuroinflammation may actively contribute to disease pathogenesis.
This project investigates the role of microglial cells in ARSACS, using an integrated in vivo and human in vitro approach. Glial behavior during neural development and disease progression has been characterized in a newly generated sacs-deficient zebrafish model. Furthermore, ARSACS patient-derived iPSC microglia has been generated to assess molecular, cellular and functional alterations. Finally, pharmacological screenings have been performed in sacs^-/- zebrafish to identify compounds capable of rescuing ARSACS-associated neuroinflammatory phenotypes.
By shifting the focus from neurons to glial cells, this work aims to redefine ARSACS as a disorder involving neuron–glia interactions and neuroinflammatory processes. Ultimately, the project seeks to uncover novel therapeutic targets and strategies for a currently untreatable neurodegenerative disease.