Image 1 - Illustration of the disruption of the internal biological clock in Machado-Joseph disease. The activity wheel — a common tool in animal behavior studies — doubles here as a clock. The orange rails mark the hours, symbolizing circadian rhythms. The background shifts from day to night, with the clock fragmenting on the night side — a metaphor for the disrupted rhythms observed in mice with the disease during their active phase. The mouse pushing the hour hand reflects the difficulty these animals have in adapting to light cycle changes, mimicking “jet lag” — one of the key dysfunctions described in the paper.
Image 2 - From left to right: Cláudia Cavadas, Rodrigo Ribeiro e Luís Pereira de Almeida.
A research team from the University of Coimbra (UC) has discovered that the internal biological clock is profoundly affected in people with Machado-Joseph disease - a rare, hereditary neurodegenerative condition that affects movement coordination, balance, speech, swallowing and other essential functions, and which has a particularly high prevalence in the Azores.
In this study, scientists from Coimbra demonstrated for the first time that this disease involves a disruption of circadian rhythms - the natural biological cycles of approximately 24 hours that regulate the functioning of the body, including sleep, body temperature and physical activity. The results of this groundbreaking study have now been published in the prestigious scientific journal BRAIN.
"What we discovered was that the circadian clock loses its robustness as the disease progresses. We also realized that the protein altered in individuals with this disease - ataxin-3 - interferes with the signals the brain sends to keep the body functioning in sync. It's as if the internal clock stops ticking properly", explains the study's first author, Rodrigo Ribeiro, researcher at the UC Center for Neuroscience and Cell Biology (CNC-UC) and the Centre for Innovative Biomedicine and Biotechnology (CiBB) and PhD student at the UC Faculty of Pharmacy (FFUC).
The research team studied circadian rhythms and characterized their disturbances, discovering reduced and more fragmented activity levels, difficulty re-entraining to sudden variations in the light-dark cycle, and dysfunctions in corebody temperature rhythms. These data reveal that those living with this disease have less regular sleep and wake times, greater difficulty adapting to changes in the environment (such as jet lag), and experience unusual changes in body temperature.
To study these rhythms, the team of scientists followed individuals diagnosed with Machado-Joseph disease using actigraphy devices, which record moments of sleep and activity. Through this monitoring, they identified severe changes in circadian rhythm parameters that correlated with the clinical progression of the disease. People with Machado-Joseph disease have, for example, a less robust and stable circadian rhythm, a greater fragmentation in activity-rest patterns, as well as a decrease in efficiency and total sleep time.
In parallel, animal and cellular models were used to study how the disease affects brain function throughout the day.
The study also reveals that the ataxin-3 protein helps to activate genes that regulate the circadian system. However, in its altered version - the mutated ataxin-3 characteristic of Machado-Joseph disease - this function is impaired. These findings help explain why circadian rhythms become disorganized as the disease progresses.
“Understanding the dysfunction of the biological clock is crucial not only to deepen our understanding of the pathophysiology of the disease, but also to establish the basis for identifying biomarkers that will allow us to monitor its progression,” adds the co-coordinator of this scientific project, president of CNC-UC, coordinator of CiBB and professor at FFUC, Luís Pereira de Almeida.
In this context, the team from the University of Coimbra hopes that, in the near future, the data revealed by this research can contribute to, for example, “testing circadian rhythm-based interventions to combat this devastating disease, and establishing actigraphy parameters - a non-invasive method for accurately monitoring activity and body temperature - that allow for a personalized assessment of its progression”, shares the coordinator of this work, CNC-UC and CiBB researcher and FFUC lecturer, Cláudia Cavadas.
Machado-Joseph disease, also known as spinocerebellar ataxia type 3, still has no cure. Therefore, this work representsan important step towards better understanding the disease and identifying new strategies that may improve the lives of those affected by it.
This work was carried out by a multidisciplinary team from the University of Coimbra, involving scientists from various research and teaching units - CNC-UC, CiBB, GeneT, the Faculty of Pharmacy, the Faculty of Science and Technology and the Faculty of Medicine - and also included the involvement of the Coimbra Local Health Unit.
The scientific article Circadian Rhythms are Disrupted in Patients and Preclinical Models of Machado-Joseph Disease is available here.
You can also watch the video about this study here.
Catarina Ribeiro with CNC-UC
