Understanding corticosterone fluctuations and HPA-axis regulation in a mouse model of Spinocerebellar ataxia type 3

Spinocerebellar ataxia type 3 (SCA3) or Machado-Joseph Disease (MJD) is a neurodegenerative disease caused by a CAG triplet expansion in the ATXN3 gene, primarily characterized by motor impairments. However, SCA3/MJD also includes mood-related comorbidities that affect both patients and their caregivers. Current treatments focus on symptom management and supportive care, as no disease-modifying therapies are available. Previously, we have demonstrated decreased glucocorticoid receptor (GR) expression in post-mortem SCA3 human and mouse brains and elevated peripheral corticosterone (CORT) levels in SCA3 mice at late disease stages. Impaired GR signaling is typically associated with hypothalamic-pituitary-adrenal (HPA) axis dysfunction, common in stress-related psychiatric diseases. Our study aimed to dissect the HPA-axis (dys)function and the effect of stress exposure on SCA3/MJD progression. Using the CMVMJD135 mouse model, we evaluated HPA-axis regulation in SCA3/MJD by measuring CORT levels throughout disease progression (6 to 34 weeks of age) under basal conditions and after acute stress. At week 35, these mice underwent a dexamethasone injection to challenge the HPA-axis, and the CORT levels were measured at different timepoints to evaluate the axis response. Additionally, we applied a 6-week chronic unpredictable stress (CUS) protocol in another cohort of mice starting at an early symptomatic stage to assess stress effects on the progression of motor impairments. Our findings indicate that serum CORT levels in SCA3 mice begin to rise between 26 to 30 weeks of age, with no impairment in the physiological response to acute stress. SCA3 mice were also able to normalize CORT levels after dexamethasone challenge, suggesting normal HPA-axis function. While CUS exposure had a transient negative impact on the motor phenotype, this effect did not persist throughout disease progression. In conclusion, stressful events, either acute or chronic, do not seem to be major determinants of disease severity in SCA3 mice.