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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. Circadian rhythms are regulated by internal clocks, with the suprachiasmatic nucleus (SCN) acting as the master pacemaker to synchronize timing across the body\u2019s 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.<\/jats:p>\n                  <jats:p>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.<\/jats:p>\n                  <jats:p>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 (\u223c1\u00b0C) 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.<\/jats:p>\n                  <jats:p>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.<\/jats:p>","DOI":"10.1093\/brain\/awaf199","type":"journal-article","created":{"date-parts":[[2025,5,27]],"date-time":"2025-05-27T07:30:27Z","timestamp":1748331027000},"page":"4127-4142","source":"Crossref","is-referenced-by-count":1,"title":["Circadian rhythms are disrupted in patients and preclinical models of Machado-Joseph disease"],"prefix":"10.1093","volume":"148","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5159-4406","authenticated-orcid":false,"given":"Rodrigo F N","family":"Ribeiro","sequence":"first","affiliation":[{"name":"Center for Neuroscience and Cell Biology (CNC-UC), University of Coimbra , Coimbra 3004-504 ,","place":["Portugal"]},{"name":"Center for Innovation in Biomedicine and Biotechnology (CIBB), University of Coimbra , Coimbra 3004-504 ,","place":["Portugal"]},{"name":"Faculty of Pharmacy, University of Coimbra (FFUC) , Coimbra 3000-548 ,","place":["Portugal"]},{"name":"Gene Therapy Center of Excellence (GeneT) , Coimbra 3004-504 ,","place":["Portugal"]}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6723-1159","authenticated-orcid":false,"given":"Dina","family":"Pereira","sequence":"additional","affiliation":[{"name":"Center for Neuroscience and Cell Biology (CNC-UC), University of Coimbra , Coimbra 3004-504 ,","place":["Portugal"]},{"name":"Center for Innovation in Biomedicine and Biotechnology (CIBB), University of Coimbra , Coimbra 3004-504 ,","place":["Portugal"]},{"name":"Gene Therapy Center of Excellence (GeneT) , Coimbra 3004-504 ,","place":["Portugal"]}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4322-8529","authenticated-orcid":false,"given":"Sara M","family":"Lopes","sequence":"additional","affiliation":[{"name":"Center for Neuroscience and Cell Biology (CNC-UC), University of Coimbra , Coimbra 3004-504 ,","place":["Portugal"]},{"name":"Center for Innovation in Biomedicine and Biotechnology (CIBB), University of Coimbra , Coimbra 3004-504 ,","place":["Portugal"]},{"name":"Gene Therapy Center of Excellence (GeneT) , Coimbra 3004-504 ,","place":["Portugal"]}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2126-2344","authenticated-orcid":false,"given":"Tiago","family":"Reis","sequence":"additional","affiliation":[{"name":"Center for Neuroscience and Cell Biology (CNC-UC), University of Coimbra , Coimbra 3004-504 ,","place":["Portugal"]},{"name":"Center for Innovation in Biomedicine and Biotechnology (CIBB), University of Coimbra , Coimbra 3004-504 ,","place":["Portugal"]},{"name":"Department of Life Sciences, Faculty of Sciences and Technology, University of Coimbra , Coimbra 3000-456 ,","place":["Portugal"]}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5436-8949","authenticated-orcid":false,"given":"Patrick","family":"Silva","sequence":"additional","affiliation":[{"name":"Center for Neuroscience and Cell Biology (CNC-UC), University of Coimbra , Coimbra 3004-504 ,","place":["Portugal"]},{"name":"Center for Innovation in Biomedicine and Biotechnology (CIBB), University of Coimbra , Coimbra 3004-504 ,","place":["Portugal"]},{"name":"Faculty of Pharmacy, University of Coimbra (FFUC) , Coimbra 3000-548 ,","place":["Portugal"]},{"name":"Gene Therapy Center of Excellence (GeneT) , Coimbra 3004-504 ,","place":["Portugal"]}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5785-4283","authenticated-orcid":false,"given":"Diana D","family":"Lobo","sequence":"additional","affiliation":[{"name":"Center for Neuroscience and Cell Biology (CNC-UC), University of Coimbra , Coimbra 3004-504 ,","place":["Portugal"]},{"name":"Center for Innovation in Biomedicine and Biotechnology (CIBB), University of Coimbra , Coimbra 3004-504 ,","place":["Portugal"]},{"name":"Gene Therapy Center of Excellence (GeneT) , Coimbra 3004-504 ,","place":["Portugal"]},{"name":"Institute for Interdisciplinary Research, University of Coimbra (iiiUC) , Coimbra 3030-789 ,","place":["Portugal"]}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9262-845X","authenticated-orcid":false,"given":"Laetitia S","family":"Gaspar","sequence":"additional","affiliation":[{"name":"Center for Neuroscience and Cell Biology (CNC-UC), University of Coimbra , Coimbra 3004-504 ,","place":["Portugal"]},{"name":"Center for Innovation in Biomedicine and Biotechnology (CIBB), University of Coimbra , Coimbra 3004-504 ,","place":["Portugal"]},{"name":"Gene Therapy Center of Excellence (GeneT) , Coimbra 3004-504 ,","place":["Portugal"]}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9671-593X","authenticated-orcid":false,"given":"Jo\u00e3o","family":"Dur\u00e3es","sequence":"additional","affiliation":[{"name":"Center for Neuroscience and Cell Biology (CNC-UC), University of Coimbra , Coimbra 3004-504 ,","place":["Portugal"]},{"name":"Center for Innovation in Biomedicine and Biotechnology (CIBB), University of Coimbra , Coimbra 3004-504 ,","place":["Portugal"]},{"name":"Department of Neurology, Coimbra Hospital and University Centre (CHUC), ULS de Coimbra , Coimbra 3004-561 ,","place":["Portugal"]},{"name":"Faculty of Medicine, University of Coimbra (FMUC) , Coimbra 3000-548 ,","place":["Portugal"]}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0250-685X","authenticated-orcid":false,"given":"Ana Rita","family":"Fernandes","sequence":"additional","affiliation":[{"name":"Center for Neuroscience and Cell Biology (CNC-UC), University of Coimbra , Coimbra 3004-504 ,","place":["Portugal"]},{"name":"Center for Innovation in Biomedicine and Biotechnology (CIBB), University of Coimbra , Coimbra 3004-504 ,","place":["Portugal"]},{"name":"Gene Therapy Center of Excellence (GeneT) , Coimbra 3004-504 ,","place":["Portugal"]},{"name":"Institute for Interdisciplinary Research, University of Coimbra (iiiUC) , Coimbra 3030-789 ,","place":["Portugal"]}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8740-6411","authenticated-orcid":false,"given":"Marisa","family":"Ferreira-Marques","sequence":"additional","affiliation":[{"name":"Center for Neuroscience and Cell Biology (CNC-UC), University of Coimbra , Coimbra 3004-504 ,","place":["Portugal"]},{"name":"Center for Innovation in Biomedicine and Biotechnology (CIBB), University of Coimbra , Coimbra 3004-504 ,","place":["Portugal"]},{"name":"Faculty of Pharmacy, University of Coimbra (FFUC) , Coimbra 3000-548 ,","place":["Portugal"]}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4942-8249","authenticated-orcid":false,"given":"Catarina","family":"Carvalhas-Almeida","sequence":"additional","affiliation":[{"name":"Center for Neuroscience and Cell Biology (CNC-UC), University of Coimbra , Coimbra 3004-504 ,","place":["Portugal"]},{"name":"Center for Innovation in Biomedicine and Biotechnology (CIBB), University of Coimbra , Coimbra 3004-504 ,","place":["Portugal"]},{"name":"Faculty of Pharmacy, University of Coimbra (FFUC) , Coimbra 3000-548 ,","place":["Portugal"]}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4989-2129","authenticated-orcid":false,"given":"Jo\u00e3o","family":"Pe\u00e7a","sequence":"additional","affiliation":[{"name":"Center for Neuroscience and Cell Biology (CNC-UC), University of Coimbra , Coimbra 3004-504 ,","place":["Portugal"]},{"name":"Center for Innovation in Biomedicine and Biotechnology (CIBB), University of Coimbra , Coimbra 3004-504 ,","place":["Portugal"]},{"name":"Department of Life Sciences, Faculty of Sciences and Technology, University of Coimbra , Coimbra 3000-456 ,","place":["Portugal"]}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2387-374X","authenticated-orcid":false,"given":"Ana Rita","family":"\u00c1lvaro","sequence":"additional","affiliation":[{"name":"Center for Neuroscience and Cell Biology (CNC-UC), University of Coimbra , Coimbra 3004-504 ,","place":["Portugal"]},{"name":"Center for Innovation in Biomedicine and Biotechnology (CIBB), University of Coimbra , Coimbra 3004-504 ,","place":["Portugal"]}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8114-9434","authenticated-orcid":false,"given":"Isabel","family":"Santana","sequence":"additional","affiliation":[{"name":"Center for Neuroscience and Cell Biology (CNC-UC), University of Coimbra , Coimbra 3004-504 ,","place":["Portugal"]},{"name":"Center for Innovation in Biomedicine and Biotechnology (CIBB), University of Coimbra , Coimbra 3004-504 ,","place":["Portugal"]},{"name":"Department of Neurology, Coimbra Hospital and University Centre (CHUC), ULS de Coimbra , Coimbra 3004-561 ,","place":["Portugal"]},{"name":"Faculty of Medicine, University of Coimbra (FMUC) , Coimbra 3000-548 ,","place":["Portugal"]}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4076-7516","authenticated-orcid":false,"given":"Magda M","family":"Santana","sequence":"additional","affiliation":[{"name":"Center for Neuroscience and Cell Biology (CNC-UC), University of Coimbra , Coimbra 3004-504 ,","place":["Portugal"]},{"name":"Center for Innovation in Biomedicine and Biotechnology (CIBB), University of Coimbra , Coimbra 3004-504 ,","place":["Portugal"]},{"name":"Gene Therapy Center of Excellence (GeneT) , Coimbra 3004-504 ,","place":["Portugal"]}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1938-4150","authenticated-orcid":false,"given":"Maria Manuel C","family":"Silva","sequence":"additional","affiliation":[{"name":"Center for Neuroscience and Cell Biology (CNC-UC), University of Coimbra , Coimbra 3004-504 ,","place":["Portugal"]},{"name":"Center for Innovation in Biomedicine and Biotechnology (CIBB), University of Coimbra , Coimbra 3004-504 ,","place":["Portugal"]},{"name":"Faculty of Pharmacy, University of Coimbra (FFUC) , Coimbra 3000-548 ,","place":["Portugal"]}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5831-3307","authenticated-orcid":false,"given":"Lu\u00eds","family":"Pereira de Almeida","sequence":"additional","affiliation":[{"name":"Center for Neuroscience and Cell Biology (CNC-UC), University of Coimbra , Coimbra 3004-504 ,","place":["Portugal"]},{"name":"Center for Innovation in Biomedicine and Biotechnology (CIBB), University of Coimbra , Coimbra 3004-504 ,","place":["Portugal"]},{"name":"Faculty of Pharmacy, University of Coimbra (FFUC) , Coimbra 3000-548 ,","place":["Portugal"]},{"name":"Gene Therapy Center of Excellence (GeneT) , Coimbra 3004-504 ,","place":["Portugal"]}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8020-9266","authenticated-orcid":false,"given":"Cl\u00e1udia","family":"Cavadas","sequence":"additional","affiliation":[{"name":"Center for Neuroscience and Cell Biology (CNC-UC), University of Coimbra , Coimbra 3004-504 ,","place":["Portugal"]},{"name":"Center for Innovation in Biomedicine and Biotechnology (CIBB), University of Coimbra , Coimbra 3004-504 ,","place":["Portugal"]},{"name":"Faculty of Pharmacy, University of Coimbra (FFUC) , Coimbra 3000-548 ,","place":["Portugal"]},{"name":"Gene Therapy Center of Excellence (GeneT) , Coimbra 3004-504 ,","place":["Portugal"]}]}],"member":"286","published-online":{"date-parts":[[2025,7,22]]},"reference":[{"key":"2025110519292303600_awaf199-B1","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1016\/S1474-4422(04)00737-9","article-title":"Autosomal dominant cerebellar ataxias: Clinical features, genetics, and pathogenesis","volume":"3","author":"Sch\u00f6ls","year":"2004","journal-title":"Lancet Neurol"},{"key":"2025110519292303600_awaf199-B2","doi-asserted-by":"crossref","first-page":"300","DOI":"10.1038\/ng0793-300","article-title":"The gene for Machado-Joseph disease maps to human chromosome 14q","volume":"4","author":"Takiyama","year":"1993","journal-title":"Nat Genet"},{"key":"2025110519292303600_awaf199-B3","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1002\/ana.410410408","article-title":"Machado-Joseph disease gene product is a cytoplasmic protein widely expressed in brain","volume":"41","author":"Paulson","year":"1997","journal-title":"Ann Neurol"},{"key":"2025110519292303600_awaf199-B4","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1038\/ng1194-221","article-title":"CAG expansions in a novel gene for Machado-Joseph disease at chromosome 14q32.1","volume":"8","author":"Kawaguchi","year":"1994","journal-title":"Nat Genet"},{"issue":"Pt 9","key":"2025110519292303600_awaf199-B5","doi-asserted-by":"crossref","first-page":"1687","DOI":"10.1093\/brain\/121.9.1687","article-title":"Autosomal dominant cerebellar ataxia type I. MRI-based volumetry of posterior fossa structures and basal ganglia in spinocerebellar ataxia types 1, 2 and 3","volume":"121","author":"Klockgether","year":"1998","journal-title":"Brain"},{"key":"2025110519292303600_awaf199-B6","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1038\/ng0696-196","article-title":"Expanded polyglutamine in the Machado-Joseph disease protein induces cell death in vitro and in vivo","volume":"13","author":"Ikeda","year":"1996","journal-title":"Nat Genet"},{"key":"2025110519292303600_awaf199-B7","doi-asserted-by":"crossref","first-page":"807","DOI":"10.1093\/hmg\/4.5.807","article-title":"Molecular features of the CAG repeats and clinical manifestation of Machado-Joseph disease","volume":"4","author":"Maruyama","year":"1995","journal-title":"Hum Mol Genet"},{"key":"2025110519292303600_awaf199-B8","doi-asserted-by":"crossref","first-page":"703","DOI":"10.1212\/WNL.28.7.703","article-title":"Autosomal dominant system degeneration in Portuguese families of the Azores Islands. A new genetic disorder involving cerebellar, pyramidal, extrapyramidal and spinal cord motor functions","volume":"28","author":"Coutinho","year":"1978","journal-title":"Neurology"},{"key":"2025110519292303600_awaf199-B9","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1111\/jnc.14541","article-title":"Machado-Joseph disease\/spinocerebellar ataxia type 3: Lessons from disease pathogenesis and clues into therapy","volume":"148","author":"Matos","year":"2019","journal-title":"J Neurochem"},{"key":"2025110519292303600_awaf199-B10","doi-asserted-by":"crossref","first-page":"11445","DOI":"10.1038\/ncomms11445","article-title":"Caloric restriction blocks neuropathology and motor deficits in Machado-Joseph disease mouse models through SIRT1 pathway","volume":"7","author":"Cunha-Santos","year":"2016","journal-title":"Nat Commun"},{"key":"2025110519292303600_awaf199-B11","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1007\/s12311-011-0252-7","article-title":"Sleep disorders in machado-joseph disease: Frequency, discriminative thresholds, predictive values, and correlation with ataxia-related motor and non-motor features","volume":"10","author":"Pedroso","year":"2011","journal-title":"Cerebellum"},{"key":"2025110519292303600_awaf199-B12","doi-asserted-by":"crossref","first-page":"100075","DOI":"10.1016\/j.nbscr.2022.100075","article-title":"Sleep disorders among Aboriginal Australians with Machado-Joseph disease: Quantitative results from a multiple methods study to assess the experience of people living with the disease and their caregivers","volume":"12","author":"LaGrappe","year":"2022","journal-title":"Neurobiol Sleep Circadian Rhythms"},{"key":"2025110519292303600_awaf199-B13","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1016\/j.sleep.2018.04.002","article-title":"Sleep apnea in Machado-Joseph disease: A clinical and polysomnographic evaluation","volume":"48","author":"Folha Santos","year":"2018","journal-title":"Sleep 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