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.