The sleep and circadian problems of Huntington’s disease: when, why and their importance

Abstract Introduction Mounting evidence supports the existence of an important feedforward cycle between sleep and neurodegeneration, wherein neurodegenerative diseases cause sleep and circadian abnormalities, which in turn exacerbate and accelerate neurodegeneration. If so, sleep therapies bear important potential to slow progression in these diseases. Findings This cycle is challenging to study, as its bidirectional nature renders cause difficult to disentangle from effect. Likewise, well-controlled intervention studies are often impractical in the setting of established neurodegenerative disease. It is this that makes understanding sleep and circadian abnormalities in Huntington’s disease (HD) important: as a monogenic fully penetrant neurodegenerative condition presenting in midlife, it provides a rare opportunity to study sleep and circadian abnormalities longitudinally, prior to and throughout disease manifestation, and in the absence of confounds rendered by age and comorbidities. It also provides potential to trial sleep therapies at a preclinical or early disease stage. Moreover, its monogenic nature facilitates the development of transgenic animal models through which to run parallel pre-clinical studies. HD, therefore, provides a key model condition through which to gain new insights into the sleep-neurodegeneration interface. Conclusions Here, we begin by summarising contemporary knowledge of sleep abnormalities in HD, and consider how well these parallel those of Alzheimer’s and Parkinson’s as more common neurodegenerative conditions. We then discuss what is currently known of the sleep-neurodegeneration cyclical relationship in HD. We conclude by outlining key directions of current and future investigation by which to advance the sleep-neurodegeneration field via studies in HD.

Download Full-text

Establishment and maintenance of an R6/1 transgenic mouse colony and validation of its progressive neurological phenotype to study Huntington’s disease

Veterinaria México OA ◽

10.21753/vmoa.5.1.487 ◽

2018 ◽

Vol 5 (1) ◽

Author(s):

Lucía Gabriela García-Lara ◽

Adriana Morales-Martínez ◽

Quetzalli Denisse Angeles-López ◽

Hilda Pedraza-Espitia ◽

Iván Pérez-Neri ◽

...

Keyword(s):

Transgenic Mice ◽

Huntington's Disease ◽

Huntington’S Disease ◽

Transgenic Mouse ◽

Neurodegenerative Disorder ◽

Transgenic Animal ◽

Phenotypic Characteristics ◽

Neurological Phenotype ◽

Transgenic Animal Models ◽

The Central Nervous System

Huntington’s disease (HD) is a hereditary neurodegenerative disorder of the central nervous system that mainly affects the basal ganglia and has no cure. The mutation is located at an abnormal expansion of the CAG triplet in the Huntingtin gene. Humans show psychiatric, behavioural and motor disorders. Transgenic animal models are essential to the study of HD since the disease only affects humans. Therefore, the aim of this article was to describe the formation and maintenance of and to validate the progressive neurological phenotype of an R6/1 transgenic mouse colony. To achieve our objective, the colony founder was imported from Jackson Laboratories, and the mice were kept under controlled environmental conditions. The animals were bred at the vivarium of the Instituto Nacional de Neurología y Neurocirugía Manuel Velasco Suárez. The R6/1 transgenic mice were successfully bred and showed genetic and phenotypic characteristics similar to the ones previously reported. Our colony is currently established and validated with the conditions of our vivarium and has produced more than four generations of R6/1 mice. The establishment of the R6/1 colony and its maintenance through generation is an advantage since it allows us to follow the authenticity of the transgenic mice regarding their phenotypic and motor behaviours. Furthermore, these animals can be compared with other transgenic mice that reproduce some of the main characteristics of the disease manifested in humans, making these transgenic R6/1 mice a useful tool for the study of HD.

Download Full-text

Is TGF-β1 a Biomarker of Huntington’s Disease Progression?

Journal of Clinical Medicine ◽

10.3390/jcm10133001 ◽

2021 ◽

Vol 10 (13) ◽

pp. 3001

Author(s):

Klaudia Plinta ◽

Andrzej Plewka ◽

Magdalena Wójcik-Pędziwiatr ◽

Nikola Zmarzły ◽

Marcin Rudziński ◽

...

Keyword(s):

Huntington's Disease ◽

Huntington’S Disease ◽

Plasma Levels ◽

Motor Dysfunction ◽

Disease Stage ◽

Control Group ◽

Early Disease ◽

Positive Correlations ◽

Early Disease Stage ◽

Tgf Β1

Huntington’s disease (HD) is an autosomal dominant genetic disease that can be divided into preclinical and symptomatic stages. Due to the diverse HD phenotype, there is an urgent need to identify markers that would independently assess its severity. The aim of this study was to evaluate the use of plasma levels of TGF-β1 in the assessment of HD severity. One hundred HD patients and 40 healthy volunteers were included in the study. All HD patients underwent neurological and cognitive function assessment. TGF-β1 levels were determined in the plasma of all patients. The correlations between TGF-β1 levels and clinical profile and HD severity were also investigated. In symptomatic patients, cognitive decline was demonstrated, while in preclinical patients, no symptoms were found. Plasma levels of TGF-β1 in HD patients did not differ significantly from the control group and did not change with the progression of the disease. In addition, TGF-β1 levels also did not correlate with the severity of motor dysfunction. Positive correlations between plasma TGF-β1 concentration and intensity of cognitive impairment were found, but only in the early disease stage. There was no clear benefit in assessing plasma TGF-β1 levels in HD patients as a marker of disease severity.

Download Full-text

Transgenic Animal Models of Huntington’s Disease

Molecular and Functional Models in Neuropsychiatry - Current Topics in Behavioral Neurosciences ◽

10.1007/7854_2010_105 ◽

2011 ◽

pp. 61-85 ◽

Cited By ~ 18

Author(s):

Shang-Hsun Yang ◽

Anthony W. S. Chan

Keyword(s):

Animal Models ◽

Huntington's Disease ◽

Huntington’S Disease ◽

Transgenic Animal ◽

Transgenic Animal Models

Download Full-text

Differential Diagnosis of Chorea—HIV Infection Delays Diagnosis of Huntington’s Disease by Years

Brain Sciences ◽

10.3390/brainsci11060710 ◽

2021 ◽

Vol 11 (6) ◽

pp. 710

Author(s):

Jannis Achenbach ◽

Simon Faissner ◽

Carsten Saft

Keyword(s):

Hiv Infection ◽

Huntington's Disease ◽

Huntington’S Disease ◽

Disease Onset ◽

Diagnostic Delay ◽

Depression Scale ◽

Cag Repeat ◽

Psychiatric Disease ◽

Disease Manifestation ◽

Cross Sectional

Background: There is a broad range of potential differential diagnoses for chorea. Besides rare, inherited neurodegenerative diseases such as Huntington’s disease (HD) chorea can accompany basal ganglia disorders due to vasculitis or infections, e.g., with the human immunodeficiency virus (HIV). The clinical picture is complicated by the rare occurrence of HIV infection and HD. Methods: First, we present a case suffering simultaneously from HIV and HD (HIV/HD) focusing on clinical manifestation and disease onset. We investigated cross-sectional data regarding molecular genetic, motoric, cognitive, functional, and psychiatric disease manifestation of HIV/HD in comparison to motor-manifest HD patients without HIV infection (nonHIV/HD) in the largest cohort of HD patients worldwide using the registry study ENROLL-HD. Data were analyzed using ANCOVA analyses controlling for covariates of age and CAG repeat length between groups in IBM SPSS Statistics V.25. Results: The HD diagnosis in our case report was delayed by approximately nine years due to the false assumption that the HIV infection might have been the cause of chorea. Out of n = 21,116 participants in ENROLL-HD, we identified n = 10,125 motor-manifest HD patients. n = 23 male participants were classified as suffering from HIV infection as a comorbidity, compared to n = 4898 male non-HIV/HD patients. Except for age, with HIV/HD being significantly younger (p < 0.050), we observed no group differences regarding sociodemographic, genetic, educational, motoric, functional, and cognitive parameters. Male HIV/HD patients reported about a 5.3-year-earlier onset of HD symptoms noticed by themselves compared to non-HIV/HD (p < 0.050). Moreover, patients in the HIV/HD group had a longer diagnostic delay of 1.8 years between onset of symptoms and HD diagnosis and a longer time regarding assessment of first symptoms by the rater and judgement of the patient (all p < 0.050). Unexpectedly, HIV/HD patients showed less irritability in the Hospital Anxiety and Depression Scale (all p < 0.05). Conclusions: The HD diagnosis in HIV-infected male patients is secured with a diagnostic delay between first symptoms noticed by the patient and final diagnosis. Treating physicians therefore should be sensitized to think of potential alternative diagnoses in HIV-infected patients also afflicted by movement disorders, especially if there is evidence of subcortical atrophy and a history of hyperkinesia, even without a clear HD-family history. Those patients should be transferred for early genetic testing to avoid further unnecessary diagnostics and improve sociomedical care.

Download Full-text

The Effects of Selective Inhibition of Histone Deacetylase 1 and 3 in Huntington’s Disease Mice

Frontiers in Molecular Neuroscience ◽

10.3389/fnmol.2021.616886 ◽

2021 ◽

Vol 14 ◽

Author(s):

Katharina Hecklau ◽

Susanne Mueller ◽

Stefan Paul Koch ◽

Mustafa Hussain Mehkary ◽

Busra Kilic ◽

...

Keyword(s):

Huntington's Disease ◽

Huntington’S Disease ◽

Selective Inhibition ◽

Skill Learning ◽

Disease Stage ◽

Therapeutic Effects ◽

Modest Improvement ◽

Symptomatic Disease ◽

Histone Deacetylase 1 ◽

Transcriptional Dysregulation

Huntington’s disease (HD) is an autosomal dominant neurodegenerative disease characterized by a late clinical onset of psychiatric, cognitive, and motor symptoms. Transcriptional dysregulation is an early and central disease mechanism which is accompanied by epigenetic alterations in HD. Previous studies demonstrated that targeting transcriptional changes by inhibition of histone deacetylases (HDACs), especially the class I HDACs, provides therapeutic effects. Yet, their exact mechanisms of action and the features of HD pathology, on which these inhibitors act remain to be elucidated. Here, using transcriptional profiling, we found that selective inhibition of HDAC1 and HDAC3 by RGFP109 alleviated transcriptional dysregulation of a number of genes, including the transcription factor genes Neurod2 and Nr4a2, and gene sets and programs, especially those that are associated to insulin-like growth factor pathway, in the striatum of R6/1 mice. RGFP109 treatment led to a modest improvement of the motor skill learning and coordination deficit on the RotaRod test, while it did not alter the locomotor and anxiety-like phenotypes in R6/1 animals. We also found, by volumetric MRI, a widespread brain atrophy in the R6/1 mice at the symptomatic disease stage, on which RGFP109 showed no significant effects. Collectively, our combined work suggests that specific HDAC1 and HDAC3 inhibition may offer benefits for alleviating the motor phenotypic deficits and transcriptional dysregulation in HD.

Download Full-text

Investigating the Transition of Pre-Symptomatic to Symptomatic Huntington’s Disease Status Based on Omics Data

International Journal of Molecular Sciences ◽

10.3390/ijms21197414 ◽

2020 ◽

Vol 21 (19) ◽

pp. 7414

Author(s):

Christiana C. Christodoulou ◽

Margarita Zachariou ◽

Marios Tomazou ◽

Evangelos Karatzas ◽

Christiana A. Demetriou ◽

...

Keyword(s):

Huntington's Disease ◽

Huntington’S Disease ◽

Transforming Growth Factor Beta ◽

Kinase Activity ◽

Transforming Growth Factor ◽

Clinical Symptoms ◽

Age Of Onset ◽

Binding Protein ◽

Biological Data ◽

Disease Stage

Huntington’s disease is a rare neurodegenerative disease caused by a cytosine–adenine–guanine (CAG) trinucleotide expansion in the Huntingtin (HTT) gene. Although Huntington’s disease (HD) is well studied, the pathophysiological mechanisms, genes and metabolites involved in HD remain poorly understood. Systems bioinformatics can reveal synergistic relationships among different omics levels and enables the integration of biological data. It allows for the overall understanding of biological mechanisms, pathways, genes and metabolites involved in HD. The purpose of this study was to identify the differentially expressed genes (DEGs), pathways and metabolites as well as observe how these biological terms differ between the pre-symptomatic and symptomatic HD stages. A publicly available dataset from the Gene Expression Omnibus (GEO) was analyzed to obtain the DEGs for each HD stage, and gene co-expression networks were obtained for each HD stage. Network rewiring, highlights the nodes that change most their connectivity with their neighbors and infers their possible implication in the transition between different states. The CACNA1I gene was the mostly highly rewired node among pre-symptomatic and symptomatic HD network. Furthermore, we identified AF198444 to be common between the rewired genes and DEGs of symptomatic HD. CNTN6, DEK, LTN1, MST4, ZFYVE16, CEP135, DCAKD, MAP4K3, NUPL1 and RBM15 between the DEGs of pre-symptomatic and DEGs of symptomatic HD and CACNA1I, DNAJB14, EPS8L3, HSDL2, SNRPD3, SOX12, ACLY, ATF2, BAG5, ERBB4, FOCAD, GRAMD1C, LIN7C, MIR22, MTHFR, NABP1, NRG2, OTC, PRAMEF12, SLC30A10, STAG2 and Y16709 between the rewired genes and DEGs of pre-symptomatic HD. The proteins encoded by these genes are involved in various biological pathways such as phosphatidylinositol-4,5-bisphosphate 3-kinase activity, cAMP response element-binding protein binding, protein tyrosine kinase activity, voltage-gated calcium channel activity, ubiquitin protein ligase activity, adenosine triphosphate (ATP) binding, and protein serine/threonine kinase. Additionally, prominent molecular pathways for each HD stage were then obtained, and metabolites related to each pathway for both disease stages were identified. The transforming growth factor beta (TGF-β) signaling (pre-symptomatic and symptomatic stages of the disease), calcium (Ca2+) signaling (pre-symptomatic), dopaminergic synapse pathway (symptomatic HD patients) and Hippo signaling (pre-symptomatic) pathways were identified. The in silico metabolites we identified include Ca2+, inositol 1,4,5-trisphosphate, sphingosine 1-phosphate, dopamine, homovanillate and L-tyrosine. The genes, pathways and metabolites identified for each HD stage can provide a better understanding of the mechanisms that become altered in each disease stage. Our results can guide the development of therapies that may target the altered genes and metabolites of the perturbed pathways, leading to an improvement in clinical symptoms and hopefully a delay in the age of onset.

Download Full-text

Disease stage and plasma levels of cytokines in Huntington's disease: A 2-year follow-up study

Movement Disorders ◽

10.1002/mds.26950 ◽

2017 ◽

Vol 32 (7) ◽

pp. 1103-1104 ◽

Cited By ~ 3

Author(s):

J.A. Bouwens ◽

E. van Duijn ◽

C.M. Cobbaert ◽

R.A.C. Roos ◽

R.C. van der Mast ◽

...

Keyword(s):

Huntington's Disease ◽

Huntington’S Disease ◽

Plasma Levels ◽

Disease Stage ◽

Follow Up Study

Download Full-text

Circadian-based Treatment Strategy Effective in the BACHD Mouse Model of Huntington’s Disease

Journal of Biological Rhythms ◽

10.1177/0748730418790401 ◽

2018 ◽

Vol 33 (5) ◽

pp. 535-554 ◽

Cited By ~ 11

Author(s):

Daniel S. Whittaker ◽

Dawn H. Loh ◽

Huei-Bin Wang ◽

Yu Tahara ◽

Dika Kuljis ◽

...

Keyword(s):

Mouse Model ◽

Huntington's Disease ◽

Huntington’S Disease ◽

Disease Progression ◽

Sleep Onset ◽

Lifestyle Changes ◽

Disease Stage ◽

Preclinical Model ◽

Delay Disease Progression ◽

Circadian Dysfunction

Huntington’s disease (HD) patients suffer from progressive neurodegeneration that results in cognitive, psychiatric, cardiovascular, and motor dysfunction. Disturbances in sleep-wake cycles are common among HD patients with reports of delayed sleep onset, frequent bedtime awakenings, and excessive fatigue. The BACHD mouse model exhibits many HD core symptoms including circadian dysfunction. Because circadian dysfunction manifests early in the disease in both patients and mouse models, we sought to determine if early interventions that improve circadian rhythmicity could benefit HD symptoms and delay disease progression. We evaluated the effects of time-restricted feeding (TRF) on the BACHD mouse model. At 3 months of age, the animals were divided into 2 groups: ad lib and TRF. The TRF-treated BACHD mice were exposed to a 6-h feeding/18-h fasting regimen that was designed to be aligned with the middle (ZT 15-21) of the period when mice are normally active (ZT 12-24). Following 3 months of treatment (when mice reached the early disease stage), the TRF-treated BACHD mice showed improvements in their locomotor activity and sleep behavioral rhythms. Furthermore, we found improved heart rate variability, suggesting that their autonomic nervous system dysfunction was improved. On a molecular level, TRF altered the phase but not the amplitude of the PER2::LUC rhythms measured in vivo and in vitro. Importantly, treated BACHD mice exhibited improved motor performance compared with untreated BACHD controls, and the motor improvements were correlated with improved circadian output. It is worth emphasizing that HD is a genetically caused disease with no known cure. Lifestyle changes that not only improve the quality of life but also delay disease progression for HD patients are greatly needed. Our study demonstrates the therapeutic potential of circadian-based treatment strategies in a preclinical model of HD.

Download Full-text