Sleep and Circadian Rhythm Dysfunction in Animal Models of Huntington’s Disease

Morton, A. Jennifer

doi:10.3233/jhd-230574

Cited by 3 publications

(3 citation statements)

References 115 publications

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“…Notably, samples from 7-year-old HD sheep exhibited an increased number of altered metabolites and a greater shift in the acrophase compared to control sheep. Furthermore, the dysregulated metabolites identified in HD sheep showed remarkable similarity to those found in human patients, particularly involving phosphatidylcholines, amino acids, urea, and threonine ( Morton, 2023 ; Spick et al, 2023 ).…”

Section: Animal Models For Hd Researchmentioning

confidence: 78%

Large animal models for Huntington’s disease research

Han,

Liang,

et al. 2024

Zoological Research

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Huntington’s disease (HD) is a hereditary neurodegenerative disorder for which there is currently no effective treatment available. Consequently, the development of appropriate disease models is critical to thoroughly investigate disease progression. The genetic basis of HD involves the abnormal expansion of CAG repeats in the huntingtin ( HTT ) gene, leading to the expansion of a polyglutamine repeat in the HTT protein. Mutant HTT carrying the expanded polyglutamine repeat undergoes misfolding and forms aggregates in the brain, which precipitate selective neuronal loss in specific brain regions. Animal models play an important role in elucidating the pathogenesis of neurodegenerative disorders such as HD and in identifying potential therapeutic targets. Due to the marked species differences between rodents and larger animals, substantial efforts have been directed toward establishing large animal models for HD research. These models are pivotal for advancing the discovery of novel therapeutic targets, enhancing effective drug delivery methods, and improving treatment outcomes. We have explored the advantages of utilizing large animal models, particularly pigs, in previous reviews. Since then, however, significant progress has been made in developing more sophisticated animal models that faithfully replicate the typical pathology of HD. In the current review, we provide a comprehensive overview of large animal models of HD, incorporating recent findings regarding the establishment of HD knock-in (KI) pigs and their genetic therapy. We also explore the utilization of large animal models in HD research, with a focus on sheep, non-human primates (NHPs), and pigs. Our objective is to provide valuable insights into the application of these large animal models for the investigation and treatment of neurodegenerative disorders.

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Section: Animal Models For Hd Researchmentioning

confidence: 78%

Large animal models for Huntington’s disease research

Han,

Liang,

et al. 2024

Zoological Research

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“…A good understanding of HD animal models is much needed for the proper interpretation of studies centered on sleep and circadian function in HD. We briefly outline major findings in these HD models as its detailed description is beyond the scope of this review [41]. Circadian rhythm studied in HD flies revealed decreased nocturnal sleep and increased sleep latency [40,41].…”

Section: Circadian Rhythm Investigations In Hdmentioning

confidence: 99%

“…We briefly outline major findings in these HD models as its detailed description is beyond the scope of this review [41]. Circadian rhythm studied in HD flies revealed decreased nocturnal sleep and increased sleep latency [40,41]. A sheep model of HD with full-length huntingtin protein and CAG repeats comparable to HD patients, exhibits sleep-wake disturbances and progressive behavior abnormalities around evening time, like the sundowning of patients with cognitive disorders, and more abrupt sleep-to-wake transitions when compared to normal sheep.…”

Section: Circadian Rhythm Investigations In Hdmentioning

confidence: 99%

Sleep Disorders and Circadian Disruption in Huntington’s Disease

Saade-Lemus

Videnović

2023

JHD

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Sleep and circadian alterations are common in patients with Huntington’s disease (HD). Understanding the pathophysiology of these alterations and their association with disease progression and morbidity can guide HD management. We provide a narrative review of the clinical and basic-science studies centered on sleep and circadian function on HD. Sleep/wake disturbances among HD patients share many similarities with other neurodegenerative diseases. Overall, HD patients and animal models of the disease present with sleep changes early in the clinical course of the disease, including difficulties with sleep initiation and maintenance leading to decreased sleep efficiency, and progressive deterioration of normal sleep architecture. Despite this, sleep alterations remain frequently under-reported by patients and under-recognized by health professionals. The degree of sleep and circadian alterations has not consistently shown to be CAG dose-dependent. Evidence based treatment recommendations are insufficient due to lack of well-designed intervention trials. Approaches aimed at improving circadian entrainment, such as including light therapy, and time-restricted feeding have demonstrated a potential to delay symptom progression in some basic HD investigations. Larger study cohorts, comprehensive assessment of sleep and circadian function, and reproducibility of findings are needed in future in order to better understand sleep and circadian function in HD and to develop effective treatments.

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Circadian Interventions in Preclinical Models of Huntington’s Disease: A Narrative Review

Dell’Angelica,

Singh,

Colwell

et al. 2024

Biomedicines

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Huntington’s Disease (HD) is a neurodegenerative disorder caused by an autosomal-dominant mutation in the huntingtin gene, which manifests with a triad of motor, cognitive and psychiatric declines. Individuals with HD often present with disturbed sleep/wake cycles, but it is still debated whether altered circadian rhythms are intrinsic to its aetiopathology or a consequence. Conversely, it is well established that sleep/wake disturbances, perhaps acting in concert with other pathophysiological mechanisms, worsen the impact of the disease on cognitive and motor functions and are a burden to the patients and their caretakers. Currently, there is no cure to stop the progression of HD, however, preclinical research is providing cementing evidence that restoring the fluctuation of the circadian rhythms can assist in delaying the onset and slowing progression of HD. Here we highlight the application of circadian-based interventions in preclinical models and provide insights into their potential translation in clinical practice. Interventions aimed at improving sleep/wake cycles’ synchronization have shown to improve motor and cognitive deficits in HD models. Therefore, a strong support for their suitability to ameliorate HD symptoms in humans emerges from the literature, albeit with gaps in our knowledge on the underlying mechanisms and possible risks associated with their implementation.

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Sleep and Circadian Rhythm Dysfunction in Animal Models of Huntington’s Disease

Cited by 3 publications

References 115 publications

Large animal models for Huntington’s disease research

Large animal models for Huntington’s disease research

Sleep Disorders and Circadian Disruption in Huntington’s Disease

Circadian Interventions in Preclinical Models of Huntington’s Disease: A Narrative Review

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