Circadian rhythms are disrupted in patients and preclinical models of Machado-Joseph disease

Jul 22, 2025Brain : a journal of neurology

Disrupted daily body clocks in patients and animal models of Machado-Joseph disease

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Abstract

patients show a progressive decline in the robustness of their behavioral rhythms over 2 weeks.

Circadian function in MJD patients correlates negatively with clinical scales of the disease, indicating more severe symptoms are linked to disrupted rhythms.
YAC-MJD mice display reduced activity and greater behavioral fragmentation compared to controls, needing more time to adjust to changes in light-dark cycles.
Core body temperature rhythms in these mice are disrupted, featuring a phase advance and a rise in temperature of approximately 1°C at the start of their active period.
Levels of neuropeptides VIP and AVP in critical brain areas are reduced in transgenic mice, suggesting alterations in the regulation of .
Clock gene expression in the cerebellum is decreased in YAC-MJD mice, which may contribute to the observed circadian disruptions.
Wild-type ATXN3 promotes the expression of certain clock-related genes, while mutant ATXN3 is unable to activate these genes effectively.

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(MJD) is caused by an abnormal CAG repeat expansion in the ATXN3 gene, leading to the expression of a mutant ataxin-3 (mutATXN3) protein. Patients with MJD exhibit a wide range of clinical symptoms, including motor incoordination. Emerging evidence highlights circadian rhythm disruptions as early indicators and potential risk factors for the progression of neurodegenerative conditions. are regulated by internal clocks, with the suprachiasmatic nucleus (SCN) acting as the master pacemaker to synchronize timing across the body's behavioural and physiological functions. While sleep disturbances have been observed in MJD, the role of clock regulation in its pathophysiology remains largely unexplored in spinocerebellar ataxias. This study aimed to investigate circadian rhythms, characterize associated disruptions and uncover the mechanisms underlying clock dysregulation in patients and preclinical models of MJD. Circadian activity in MJD patients was assessed over 2 weeks using actigraphy, while in a YAC-MJD transgenic mouse model, circadian rhythms were examined through: (i) wheel-running experiments; (ii) telemetry-based monitoring of core body temperature; (iii) immunohistochemical analysis of the neuropeptides arginine vasopressin (AVP) and vasoactive intestinal polypeptide (VIP) in the SCN and paraventricular nucleus (PVN); and (iv) quantitative real-time PCR evaluation of clock gene expression in the cerebellum. The impact of mutATXN3 on clock mechanisms was further investigated using Bmal1/Per2-luciferase reporters. MJD patients exhibited a progressive decline in robustness of behavioural rhythms, demonstrated by negative correlations between the circadian function index, rest-activity fragmentation and sleep efficiency with MJD clinical scales. YAC-MJD mice exhibited reduced activity levels and increased behavioural fragmentation, and they required three additional days to re-entrain after a jet lag protocol compared to controls. Disrupted core body temperature rhythms were observed, including a phase advance and elevated temperature (∼1°C) at the onset of the active period. Furthermore, transgenic mice showed reduced levels of VIP and AVP in the SCN and PVN and decreased clock gene expression in the cerebellum. Lastly, we found new mechanistic evidence that wild-type ATXN3 activates the promoters of Bmal1 and Per2, whereas mutATXN3 loses the capacity to drive Per2 upon polyglutamine expansion. Overall, our findings indicate that central clock dysfunction in MJD is associated with impaired clock gene expression and disruptions in activity and temperature rhythms. This study provides the first robust evidence of circadian rhythm dysregulation and underlying mechanisms in MJD, paving the way for identifying new biomarkers and developing novel circadian-based interventions to tackle MJD and possibly other spinocerebellar ataxias.

Key numbers

−0.9073

Decrease in Circadian Function Index

Correlation between CFI and SARA score in patients.

53%

Activity reduction in YAC- mice

Overall activity level during the study compared to wild-type mice.

1.08°C

Core body temperature increase

Maximum increase in core body temperature observed in homozygous mice.

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Circadian rhythms are disrupted in patients and preclinical models of Machado-Joseph disease

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