Long-Term Benefits of TUDCA Supplement in ARSACS Zebrafish Model

Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS ) is an early-onset neurodevelopmental and neurodegenerative disorder characterized by ataxia, spasticity, and peripheral neuropathy. However, several studies have highlighted that some patients also experience cognitive, emotional and social deficits, suggesting a more complex clinical picture that extends beyond motor symptoms. Building on these findings, this study aimed to: i) investigate locomotor, social and cognitive deficits in adult sacs ^-/- zebrafish versus wild-type (WT) controls through behavioural tests; ii) identify molecular patterns associated with the adult disease phenotype using transcriptomic and proteomic analyses of sacs ^-/- and WT brains; iii) evaluate the effectiveness of long-term treatment with tauroursodeoxycholic acid (TUDCA) on behavioural outcomes and omics profiles in the zebrafish sacs ^-/- model. Our findings indicate impairments in cognitive, social, and emotional behaviors in aged sacs ^-/- zebrafish, which resemble some deficits observed in human patients. Transcriptomic and proteomic analyses of adult brains identified alterations in genes related to circadian rhythms and neuroinflammation. Notably, disruptions in sleep and circadian rhythms are frequently reported in individuals with cerebellar ataxia and may contribute to cognitive and behavioral changes. Long-term treatment with TUDCA, a neuroprotective molecule, was associated with partial improvements in social and cognitive behaviors and modifications in omics profiles in the zebrafish model. These results support the potential of further exploring TUDCA in future preclinical and clinical studies, while also emphasizing the need for additional investigations to better understand its mechanisms of action.