INCREASED CORTICOSTERONE LEVELS AND ENHANCED RESPONSE TO ACUTE STRESS IN A SCA3 MOUSE MODEL

Spinocerebellar ataxia type 3 (SCA3) is a neurodegenerative disease caused by a CAG triplet expansion in the ATXN3 gene. SCA3 affects mainly motor function, but patients often report depression and anxiety. Indeed, SCA3 mice exhibited elevated levels of serum corticosterone, common to mood-related symptomatology. A reduction of glucocorticoid receptor (GR) was found in the brainstem of SCA3 mice and post-mortem brain samples from SCA3 patients. To evaluate the regulation of the hypothalamic-pituitary-adrenal (HPA)-axis in SCA3 mice, quantification of corticosterone was conducted throughout disease progression under basal conditions (nadir/zenith) and after an acute stressor. To challenge the HPA-axis, SCA3 mice were submitted to a dexamethasone injection at a later stage (35-weeks-old). Data suggests a sustained serum corticosterone elevation starting between 26 to 30 weeks of age, as well as an overactive physiological response to an acute stressor, with a possible delayed recovery of corticosterone levels. Nevertheless, SCA3 mice were able to restore corticosterone levels after a challenge with dexamethasone, suggesting functional negative feedback within the HPA-axis. To simulate negative prospects of the disease and assess the interference of stress on motor impairments, a 6-weeks chronic unpredictable stress (CUS) protocol was applied at an early symptomatic stage. However, exposure of SCA3 mice to CUS did not impact motor phenotype, indicating that stress is not a major determinant for disease severity. Further analyses of GR levels in the hypothalamus of SCA3 mice are being conducted to better understand the peripheral increase of corticosterone and the involvement of this hormonal axis in SCA3 pathology.