Investigating TUDCA for Spinocerebellar Ataxia Type 3 (SCA3): The Role of Caenorhabditis elegans

The exploration of tauroursodeoxycholic acid (TUDCA) as a therapeutic for Spinocerebellar Ataxia Type 3 (SCA3) has yielded promising results, with research spearheaded by Dr. Andreia Teixeira-Castro and Dr. Patrícia Maciel at the University of Minho. A key aspect of this research was the use of Caenorhabditis elegans as an initial model organism.

The researcher's team employed transgenic C. elegans expressing the mutant ataxin-3 protein, which is associated with SCA3. TUDCA emerged as a promising candidate, demonstrating significant improvements in the motor and neuropathological phenotypes of these nematodes.

Initial findings in C. elegans provided a solid foundation for further studies in more complex models, such as transgenic mice. The research revealed that TUDCA exerts its neuroprotective effects through the glucocorticoid receptor (GR) rather than its canonical receptor, the farnesoid X receptor (FXR). This discovery suggests a novel in vivo mechanism for TUDCA's action and supports its potential for clinical trials in SCA3 patients.

The journey of TUDCA from initial discovery in C. elegans to validation in higher organisms highlights the power of using simple model organisms to accelerate drug discovery. This approach not only facilitated the rapid identification of a potential therapeutic but also provided valuable insights into its mechanism of action, paving the way for future clinical applications in treating complex human diseases like SCA3.

Duarte-Silva S, Da Silva JD, Monteiro-Fernandes D, Costa MD, Neves-Carvalho A, Raposo M, Soares-Cunha C, Correia JS, Nogueira-Goncalves G, Fernandes HS, Oliveira S, Ferreira-Fernandes AR, Rodrigues F, Pereira-Sousa J, Vilasboas-Campos D, Guerreiro S, Campos J, Meireles-Costa L, Rodrigues CMP, Cabantous S, Sousa SF, Lima M, Teixeira-Castro A, Maciel P. Glucocorticoid receptor-dependent therapeutic efficacy of tauroursodeoxycholic acid in preclinical models of spinocerebellar ataxia type 3. J Clin Invest. 2024 Mar 1;134(5):e162246. doi: 10.1172/JCI162246.