Glucocorticoid receptor-dependent therapeutic efficacy of tauroursodeoxycholic acid in preclinical models of spinocerebellar ataxia type 3
Sara Duarte-Silva, … , Andreia Teixeira-Castro, Patricia Maciel
Sara Duarte-Silva, … , Andreia Teixeira-Castro, Patricia Maciel
Published January 16, 2024
Citation Information: J Clin Invest. 2024;134(5):e162246. https://doi.org/10.1172/JCI162246.
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Research Article Neuroscience

Glucocorticoid receptor-dependent therapeutic efficacy of tauroursodeoxycholic acid in preclinical models of spinocerebellar ataxia type 3

Abstract

Spinocerebellar ataxia type 3 (SCA3) is an adult-onset neurodegenerative disease caused by a polyglutamine expansion in the ataxin-3 (ATXN3) gene. No effective treatment is available for this disorder, other than symptom-directed approaches. Bile acids have shown therapeutic efficacy in neurodegenerative disease models. Here, we pinpointed tauroursodeoxycholic acid (TUDCA) as an efficient therapeutic, improving the motor and neuropathological phenotype of SCA3 nematode and mouse models. Surprisingly, transcriptomic and functional in vivo data showed that TUDCA acts in neuronal tissue through the glucocorticoid receptor (GR), but independently of its canonical receptor, the farnesoid X receptor (FXR). TUDCA was predicted to bind to the GR, in a similar fashion to corticosteroid molecules. GR levels were decreased in disease-affected brain regions, likely due to increased protein degradation as a consequence of ATXN3 dysfunction being restored by TUDCA treatment. Analysis of a SCA3 clinical cohort showed intriguing correlations between the peripheral expression of GR and the predicted age at disease onset in presymptomatic subjects and FKBP5 expression with disease progression, suggesting this pathway as a potential source of biomarkers for future study. We have established a novel in vivo mechanism for the neuroprotective effects of TUDCA in SCA3 and propose this readily available drug for clinical trials in SCA3 patients.

Authors

Sara Duarte-Silva, Jorge Diogo Da Silva, Daniela Monteiro-Fernandes, Marta Daniela Costa, Andreia Neves-Carvalho, Mafalda Raposo, Carina Soares-Cunha, Joana S. Correia, Gonçalo Nogueira-Goncalves, Henrique S. Fernandes, Stephanie Oliveira, Ana Rita Ferreira-Fernandes, Fernando Rodrigues, Joana Pereira-Sousa, Daniela Vilasboas-Campos, Sara Guerreiro, Jonas Campos, Liliana Meireles-Costa, Cecilia M.P. Rodrigues, Stephanie Cabantous, Sergio F. Sousa, Manuela Lima, Andreia Teixeira-Castro, Patricia Maciel

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Figure 1

Impact of BAs on the motor phenotype of SCA3 nematode and mouse models.

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Impact of BAs on the motor phenotype of SCA3 nematode and mouse models. ...
(A) Percentage of improvement in locomotion-defective animals of a representative set of BAs. The predetermined optimal concentration for each compound was used. A total of 3-to-4 independent experiments were performed, for a total of 150–200 animals assayed. (B) Dose-response evaluation of the effect of TUDCA in reducing the percentage of locomotion-defective AT3Q130 animals. AT3Q75 animals were used as a TG non-motor-defective control, and 1% DMSO was used as the negative control for vehicle administration. A total of 3-to-4 independent experiments with 150–200 animals were performed. (C) Kaplan-Meyer curve of the survival of AT3Q130 nematodes treated with TUDCA. The daf-2 and daf-16 strains were used as long and short-lived controls, respectively. A total of 300 animals per condition were tested along 3 independent experiments. (D) Evaluation of the time taken for a mouse to cross a 12 mm square beam, with TUDCA having a positive effect. (E) Assessment of the time taken for a mouse to swim through a 60 cm water path. TUDCA consistently improved this time throughout the trial. #, no difference between WT and TG TUDCA animals. (F) Gait quality was improved in treated animals. (G) The strength of an animal to grab a grid was used to evaluate forelimb strength. TUDCA had a positive effect in some time points. (H) Qualitative assessment of limb clasping revealed a significant improvement of TG TUDCA-treated animals in comparison with TG. Black *, WT versus TG; red *, TG versus TG TUDCA. A total of 14–17 mice per condition was used in all tests and evaluated in the indicated weeks of age. 1-way ANOVA (B, D, and E). Kaplan Meier and Cox regression (C). κ2 test (F–H). * P < 0.05, ** P < 0.01, *** P < 0.001.