A selective inhibitor of histone deacetylase 3 prevents cognitive deficits and suppresses striatal CAG repeat expansions in Huntington’s disease mice

Abstract Huntington’s disease (HD) is a fatal, inherited neurodegenerative disease that causes neuronal death, particularly in medium spiny neurons. HD leads to serious and progressive motor, cognitive and psychiatric symptoms. Its genetic basis is an expansion of the CAG triplet repeat in the HTT gene, leading to extra glutamines in the huntingtin protein. HD is one of nine genetic diseases in this polyglutamine (polyQ) category, that also includes a number of inherited spinocerebellar ataxias (SCAs). Traditionally it has been assumed that HD age of onset and disease progression were solely the outcome of age-dependent exposure of neurons to toxic effects of the inherited mutant huntingtin protein. However, recent genome-wide association studies (GWAS) have revealed significant effects of genetic variants outside of HTT. Surprisingly, these variants turn out to be mostly in genes encoding DNA repair factors, suggesting that at least some disease modulation occurs at the level of the HTT DNA itself. These DNA repair proteins are known from model systems to promote ongoing somatic CAG repeat expansions in tissues affected by HD. Thus, for triplet repeats, some DNA repair proteins seem to abandon their normal genoprotective roles and, instead, drive expansions and accelerate disease. One attractive hypothesis—still to be proven rigorously—is that somatic HTT expansions augment the disease burden of the inherited allele. If so, therapeutic approaches that lower levels of huntingtin protein may need blending with additional therapies that reduce levels of somatic CAG repeat expansions to achieve maximal effect.

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Impaired Brain Energy Metabolism in the BACHD Mouse Model of Huntington's Disease: Critical Role of Astrocyte–Neuron Interactions

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.2014.110 ◽

2014 ◽

Vol 34 (9) ◽

pp. 1500-1510 ◽

Cited By ~ 25

Author(s):

Lydie Boussicault ◽

Anne-Sophie Hérard ◽

Noel Calingasan ◽

Fanny Petit ◽

Carole Malgorn ◽

...

Keyword(s):

Energy Metabolism ◽

Huntington's Disease ◽

Huntington’S Disease ◽

Molecular Mechanisms ◽

Critical Role ◽

Cag Repeat ◽

Metabolic Alterations ◽

Culture Models ◽

Repeat Expansions

Huntington's disease (HD) is caused by cytosine-adenine-guanine (CAG) repeat expansions in the huntingtin (Htt) gene. Although early energy metabolic alterations in HD are likely to contribute to later neurodegenerative processes, the cellular and molecular mechanisms responsible for these metabolic alterations are not well characterized. Using the BACHD mice that express the full-length mutant huntingtin (mHtt) protein with 97 glutamine repeats, we first demonstrated localized in vivo changes in brain glucose use reminiscent of what is observed in premanifest HD carriers. Using biochemical, molecular, and functional analyses on different primary cell culture models from BACHD mice, we observed that mHtt does not directly affect metabolic activity in a cell autonomous manner. However, coculture of neurons with astrocytes from wild-type or BACHD mice identified mutant astrocytes as a source of adverse non-cell autonomous effects on neuron energy metabolism possibly by increasing oxidative stress. These results suggest that astrocyte-to-neuron signaling is involved in early energy metabolic alterations in HD.

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The Effects of Pharmacological Inhibition of Histone Deacetylase 3 (HDAC3) in Huntington’s Disease Mice

PLoS ONE ◽

10.1371/journal.pone.0152498 ◽

2016 ◽

Vol 11 (3) ◽

pp. e0152498 ◽

Cited By ~ 41

Author(s):

Haiqun Jia ◽

Ying Wang ◽

Charles D. Morris ◽

Vincent Jacques ◽

Joel M. Gottesfeld ◽

...

Keyword(s):

Huntington's Disease ◽

Huntington’S Disease ◽

Histone Deacetylase ◽

Histone Deacetylase 3 ◽

Pharmacological Inhibition

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Fluorescence PCR and GeneScan® Analysis for the Detection of CAG Repeat Expansions Associated with Huntington's Disease

Neurogenetics ◽

10.1385/1-59259-330-5:101 ◽

2003 ◽

pp. 101-108

Author(s):

Cindy L. Vnencak-Jones

Keyword(s):

Huntington's Disease ◽

Huntington’S Disease ◽

Cag Repeat ◽

Repeat Expansions

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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.

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The Contribution of Somatic Expansion of the CAG Repeat to Symptomatic Development in Huntington’s Disease: A Historical Perspective

Journal of Huntington s Disease ◽

10.3233/jhd-200429 ◽

2021 ◽

Vol 10 (1) ◽

pp. 7-33

Author(s):

Darren G. Monckton

Keyword(s):

Huntington's Disease ◽

Huntington’S Disease ◽

Human Genetics ◽

Age At Onset ◽

Cag Repeat ◽

Model Systems ◽

Causative Mutation ◽

Inverse Association ◽

Independent Manner ◽

Dna Mismatch

The discovery in the early 1990s of the expansion of unstable simple sequence repeats as the causative mutation for a number of inherited human disorders, including Huntington’s disease (HD), opened up a new era of human genetics and provided explanations for some old problems. In particular, an inverse association between the number of repeats inherited and age at onset, and unprecedented levels of germline instability, biased toward further expansion, provided an explanation for the wide symptomatic variability and anticipation observed in HD and many of these disorders. The repeats were also revealed to be somatically unstable in a process that is expansion-biased, age-dependent and tissue-specific, features that are now increasingly recognised as contributory to the age-dependence, progressive nature and tissue specificity of the symptoms of HD, and at least some related disorders. With much of the data deriving from affected individuals, and model systems, somatic expansions have been revealed to arise in a cell division-independent manner in critical target tissues via a mechanism involving key components of the DNA mismatch repair pathway. These insights have opened new approaches to thinking about how the disease could be treated by suppressing somatic expansion and revealed novel protein targets for intervention. Exciting times lie ahead in turning these insights into novel therapies for HD and related disorders.

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Targeting CAG repeat RNAs reduces Huntington’s disease phenotype independently of huntingtin levels

Journal of Clinical Investigation ◽

10.1172/jci83185 ◽

2016 ◽

Vol 126 (11) ◽

pp. 4319-4330 ◽

Cited By ~ 32

Author(s):

Laura Rué ◽

Mónica Bañez-Coronel ◽

Jordi Creus-Muncunill ◽

Albert Giralt ◽

Rafael Alcalá-Vida ◽

...

Keyword(s):

Huntington's Disease ◽

Huntington’S Disease ◽

Cag Repeat ◽

Disease Phenotype

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Skeletal muscle regeneration is altered in the R6/2 mouse model of Huntington's disease

10.1101/2022.01.11.475914 ◽

2022 ◽

Author(s):

Sanzana Hoque ◽

Marie Sjogren ◽

Valerie Allamand ◽

Kinga Gawlik ◽

Naomi Franke ◽

...

Keyword(s):

Skeletal Muscle ◽

Huntington's Disease ◽

Huntington’S Disease ◽

Muscle Damage ◽

Satellite Cell ◽

Mouse Models ◽

Satellite Cells ◽

Muscle Fibers ◽

Cag Repeat ◽

Skeletal Muscle Regeneration

Huntington's disease (HD) is caused by CAG repeat expansion in the huntingtin (HTT) gene. Skeletal muscle wasting alongside central pathology is a well-recognized phenomenon seen in patients with HD and HD mouse models. HD muscle atrophy progresses with disease and affects prognosis and quality of life. Satellite cells, progenitors of mature skeletal muscle fibers, are essential for proliferation, differentiation, and repair of muscle tissue in response to muscle injury or exercise. In this study, we aim to investigate the effect of mutant HTT on the differentiation and regeneration capacity of HD muscle by employing in vitro mononuclear skeletal muscle cell isolation and in vivo acute muscle damage model in R6/2 mice. We found that, similar to R6/2 adult mice, neonatal R6/2 mice also exhibit a significant reduction in myofiber width and morphological changes in gastrocnemius and soleus muscles compared to WT mice. Cardiotoxin (CTX)-induced acute muscle damage in R6/2 and WT mice showed that the Pax7+ satellite cell pool was dampened in R6/2 mice at 4 weeks post-injection, and R6/2 mice exhibited an altered inflammatory profile in response to acute damage. Our results suggest that, in addition to the mutant HTT degenerative effects in mature muscle fibers, expression of mutant HTT in satellite cells might alter developmental and regenerative processes to contribute to the progressive muscle mass loss in HD. Taken together, the results presented here encourage further studies evaluating the underlying mechanisms of satellite cell dysfunction in HD mouse models.

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