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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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 7

GR interacts with WT and mutant ATXN3, and is translocated to the nucleus upon TUDCA treatment.

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GR interacts with WT and mutant ATXN3, and is translocated to the nucleu...
(A) Immunoprecipitation followed by Western blot showed coimmunoprecipitation of GR with ATXN3 (rabbit anti-ATXN3, MJD1-1) from mouse brain tissue lysates. IB, immunoblotting done with antibody against either GR or ATXN3 (mouse anti-ATXN3, 1H9). IP, immunoprecipitation done with an antibody against ATXN3. NC, isotype control antibody of the same isotype as the primary antibodies to discern specific binding from nonspecific interactions. A 40% increase in image contrast was applied from the original blots. (B) Representative fluorescence microphotographs of SH-SY5Y cells following DAPI staining and a PLA of GR and ATXN3, in both WT and cells with shRNA-mediated knockdown (KD) of ATXN3 expression. The negative control represents absence of primary antibodies, and ATXN3 KD cells show a scarcer signal compared with WT cells, as expected. Scale bars, 50 μm. (C) Tripartite split-GFP system fluorescence in MRC5-SV cells expressing GFP1-9. Cells were transfected with GR fused with GFP10 and ATXN3 fused with GFP11 (14Q or 78Q) and treated with and TUDCA at 100 μM for 24 hours. Upon protein interaction, GFP10 and GFP11 assemble, spontaneously associate with GFP1-9, and fluorescence is emitted. Green fluorescence at 488 nm excitation (GFP), DAPI nuclear staining (blue). Scale bars: 100 μm and 20 μm (inset). (D) Quantification of the percentage of the cellular area with colocalization of both GFP and DAPI signal in Q14 and (E) Q78 expressing cells with vehicle or TUDCA treatment. Mann-Whitney U test, *** P < 0.001.