scholarly journals Modifiers of Somatic Repeat Instability in Mouse Models of Friedreich Ataxia and the Fragile X-Related Disorders: Implications for the Mechanism of Somatic Expansion in Huntington’s Disease

2021 ◽  
Vol 10 (1) ◽  
pp. 149-163
Author(s):  
Xiaonan Zhao ◽  
Daman Kumari ◽  
Carson J. Miller ◽  
Geum-Yi Kim ◽  
Bruce Hayward ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Mouse Models ◽  
Fragile X ◽  
Friedreich Ataxia ◽  
Disease Onset ◽  
Neuronal Cell ◽  
Repeat Expansion ◽  
Cag Repeat ◽  
Dna Repeats

Huntington’s disease (HD) is one of a large group of human disorders that are caused by expanded DNA repeats. These repeat expansion disorders can have repeat units of different size and sequence that can be located in any part of the gene and, while the pathological consequences of the expansion can differ widely, there is evidence to suggest that the underlying mutational mechanism may be similar. In the case of HD, the expanded repeat unit is a CAG trinucleotide located in exon 1 of the huntingtin (HTT) gene, resulting in an expanded polyglutamine tract in the huntingtin protein. Expansion results in neuronal cell death, particularly in the striatum. Emerging evidence suggests that somatic CAG expansion, specifically expansion occurring in the brain during the lifetime of an individual, contributes to an earlier disease onset and increased severity. In this review we will discuss mouse models of two non-CAG repeat expansion diseases, specifically the Fragile X-related disorders (FXDs) and Friedreich ataxia (FRDA). We will compare and contrast these models with mouse and patient-derived cell models of various other repeat expansion disorders and the relevance of these findings for somatic expansion in HD. We will also describe additional genetic factors and pathways that modify somatic expansion in the FXD mouse model for which no comparable data yet exists in HD mice or humans. These additional factors expand the potential druggable space for diseases like HD where somatic expansion is a significant contributor to disease impact.

scholarly journals A Patient-Derived Cellular Model for Huntington’s Disease Reveals Phenotypes at Clinically Relevant CAG Lengths

2018 ◽  
Author(s):  
Claudia Lin-Kar Hung ◽  
Tamara Maiuri ◽  
Laura Erin Bowie ◽  
Ryan Gotesman ◽  
Susie Son ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Cell Lines ◽  
Disease Onset ◽  
Cag Repeat ◽  
Dna Repeats ◽  
Cellular Model ◽  
Human Telomerase Reverse Transcriptase ◽  
Huntingtin Protein ◽  
Transformed Cell Lines

ABSTRACTThe huntingtin protein participates in several cellular processes that are disrupted when the polyglutamine tract is expanded beyond a threshold of 37 CAG DNA repeats in Huntington’s disease (HD). Cellular biology approaches to understand these functional disruptions in HD have primarily focused on cell lines with synthetically long CAG length alleles that clinically represent outliers in this disease and a more severe form of HD that lacks age-onset. Patient-derived fibroblasts are limited to a finite number of passages before succumbing to cellular senescence. We used human telomerase reverse transcriptase (hTERT) to immortalize fibroblasts taken from individuals of varying age, sex, disease onset and CAG repeat length, which we have termed TruHD cells. TruHD cells display classic HD phenotypes of altered morphology, size and growth rate, increased sensitivity to oxidative stress, aberrant ADP/ATP ratios and hypophosphorylated huntingtin protein. We additionally observed dysregulated ROS-dependent huntingtin localization to nuclear speckles in HD cells. We report the generation and characterization of a human, clinically relevant cellular model for investigating disease mechanisms in HD at the single cell level, which, unlike transformed cell lines, maintains TP53 function critical for huntingtin transcriptional regulation and genomic integrity.

scholarly journals Striatal Circuit Development and Its Alterations in Huntington’s Disease

2020 ◽  
Author(s):  
Margaux Lebouc ◽  
Quentin Richard ◽  
Maurice Garret ◽  
Jérôme Baufreton
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Mouse Models ◽  
Neurodegenerative Disorder ◽  
Repeat Expansion ◽  
Cag Repeat ◽  
Rodent Models ◽  
Network Development ◽  
Cag Repeat Expansion ◽  
Circuit Development

Huntington's disease (HD) is an inherited neurodegenerative disorder that usually starts during midlife with progressive alterations of motor and cognitive functions. The disease is caused by a CAG repeat expansion within the huntingtin gene leading to severe striatal neurodegeneration. Recent studies conducted on pre-HD children highlight early striatal developmental alterations starting as soon as 6 years old, the earliest age assessed. These findings, in line with data from mouse models of HD, raise the question of when during development do the first disease-related striatal alterations emerge or whether they contribute to the later appearance of the neurodegenerative features of the disease. In this review we will describe the different stages of striatal network development and then discuss recent evidence for its alterations in rodent models of the disease. We argue that a better understanding of the striatum’s development should help in assessing aberrant neurodevelopmental processes linked to the HD mutation.

scholarly journals A patient-derived cellular model for Huntington’s disease reveals phenotypes at clinically relevant CAG lengths

2018 ◽  
Vol 29 (23) ◽  
pp. 2809-2820 ◽  
Author(s):  
Claudia Lin-Kar Hung ◽  
Tamara Maiuri ◽  
Laura Erin Bowie ◽  
Ryan Gotesman ◽  
Susie Son ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Cell Lines ◽  
Disease Onset ◽  
Cag Repeat ◽  
Dna Repeats ◽  
Cellular Model ◽  
Human Telomerase Reverse Transcriptase ◽  
Huntingtin Protein ◽  
Transformed Cell Lines

The huntingtin protein participates in several cellular processes that are disrupted when the polyglutamine tract is expanded beyond a threshold of 37 CAG DNA repeats in Huntington’s disease (HD). Cellular biology approaches to understand these functional disruptions in HD have primarily focused on cell lines with synthetically long CAG length alleles that clinically represent outliers in this disease and a more severe form of HD that lacks age onset. Patient-derived fibroblasts are limited to a finite number of passages before succumbing to cellular senescence. We used human telomerase reverse transcriptase (hTERT) to immortalize fibroblasts taken from individuals of varying age, sex, disease onset, and CAG repeat length, which we have termed TruHD cells. TruHD cells display classic HD phenotypes of altered morphology, size and growth rate, increased sensitivity to oxidative stress, aberrant adenosine diphosphate/adenosine triphosphate (ADP/ATP) ratios, and hypophosphorylated huntingtin protein. We additionally observed dysregulated reactive oxygen species (ROS)-dependent huntingtin localization to nuclear speckles in HD cells. We report the generation and characterization of a human, clinically relevant cellular model for investigating disease mechanisms in HD at the single-cell level, which, unlike transformed cell lines, maintains functions critical for huntingtin transcriptional regulation and genomic integrity.

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

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.

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

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.

scholarly journals Juvenile Huntington’s Disease and Other PolyQ Diseases, Update on Neurodevelopmental Character and Comparative Bioinformatic Review of Transcriptomic and Proteomic Data

2021 ◽  
Vol 9 ◽  
Author(s):  
Karolina Świtońska-Kurkowska ◽  
Bart Krist ◽  
Joanna Delimata ◽  
Maciej Figiel
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Mouse Models ◽  
Muscular Atrophy ◽  
Expression Patterns ◽  
Cag Repeat ◽  
Human Cognition ◽  
Expression Data ◽  
Neuronal Stem Cell ◽  
Polyq Diseases

Polyglutamine (PolyQ) diseases are neurodegenerative disorders caused by the CAG repeat expansion mutation in affected genes resulting in toxic proteins containing a long chain of glutamines. There are nine PolyQ diseases: Huntington’s disease (HD), spinocerebellar ataxias (types 1, 2, 3, 6, 7, and 17), dentatorubral-pallidoluysian atrophy (DRPLA), and spinal bulbar muscular atrophy (SBMA). In general, longer CAG expansions and longer glutamine tracts lead to earlier disease presentations in PolyQ patients. Rarely, cases of extremely long expansions are identified for PolyQ diseases, and they consistently lead to juvenile or sometimes very severe infantile-onset polyQ syndromes. In apparent contrast to the very long CAG tracts, shorter CAGs and PolyQs in proteins seems to be the evolutionary factor enhancing human cognition. Therefore, polyQ tracts in proteins can be modifiers of brain development and disease drivers, which contribute neurodevelopmental phenotypes in juvenile- and adult-onset PolyQ diseases. Therefore we performed a bioinformatics review of published RNAseq polyQ expression data resulting from the presence of polyQ genes in search of neurodevelopmental expression patterns and comparison between diseases. The expression data were collected from cell types reflecting stages of development such as iPSC, neuronal stem cell, neurons, but also the adult patients and models for PolyQ disease. In addition, we extended our bioinformatic transcriptomic analysis by proteomics data. We identified a group of 13 commonly downregulated genes and proteins in HD mouse models. Our comparative bioinformatic review highlighted several (neuro)developmental pathways and genes identified within PolyQ diseases and mouse models responsible for neural growth, synaptogenesis, and synaptic plasticity.

scholarly journals MSH3 modifies somatic instability and disease severity in Huntington’s and myotonic dystrophy type 1

Brain ◽  
2019 ◽  
Vol 142 (7) ◽  
pp. 1876-1886 ◽  
Author(s):  
Michael Flower ◽  
Vilija Lomeikaite ◽  
Marc Ciosi ◽  
Sarah Cumming ◽  
Fernando Morales ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Association Study ◽  
Huntington’S Disease ◽  
Myotonic Dystrophy ◽  
Disease Onset ◽  
Repeat Expansion ◽  
Myotonic Dystrophy Type 1 ◽  
Myotonic Dystrophy Type ◽  
Exon 1

Abstract The mismatch repair gene MSH3 has been implicated as a genetic modifier of the CAG·CTG repeat expansion disorders Huntington’s disease and myotonic dystrophy type 1. A recent Huntington’s disease genome-wide association study found rs557874766, an imputed single nucleotide polymorphism located within a polymorphic 9 bp tandem repeat in MSH3/DHFR, as the variant most significantly associated with progression in Huntington’s disease. Using Illumina sequencing in Huntington’s disease and myotonic dystrophy type 1 subjects, we show that rs557874766 is an alignment artefact, the minor allele for which corresponds to a three-repeat allele in MSH3 exon 1 that is associated with a reduced rate of somatic CAG·CTG expansion (P = 0.004) and delayed disease onset (P = 0.003) in both Huntington’s disease and myotonic dystrophy type 1, and slower progression (P = 3.86 × 10−7) in Huntington’s disease. RNA-Seq of whole blood in the Huntington’s disease subjects found that repeat variants are associated with MSH3 and DHFR expression. A transcriptome-wide association study in the Huntington’s disease cohort found increased MSH3 and DHFR expression are associated with disease progression. These results suggest that variation in the MSH3 exon 1 repeat region influences somatic expansion and disease phenotype in Huntington’s disease and myotonic dystrophy type 1, and suggests a common DNA repair mechanism operates in both repeat expansion diseases.

scholarly journals Conformational studies of pathogenic expanded polyglutamine protein deposits from Huntington’s disease

2019 ◽  
Vol 244 (17) ◽  
pp. 1584-1595 ◽  
Author(s):  
Irina Matlahov ◽  
Patrick CA van der Wel
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Structural Biology ◽  
Age Of Onset ◽  
Repeat Expansion ◽  
Cag Repeat ◽  
Mutant Huntingtin ◽  
Cag Repeat Expansion ◽  
Recent Developments ◽  
Mutant Huntingtin Protein

Huntington’s disease, like other neurodegenerative diseases, continues to lack an effective cure. Current treatments that address early symptoms ultimately fail Huntington’s disease patients and their families, with the disease typically being fatal within 10–15 years from onset. Huntington’s disease is an inherited disorder with motor and mental impairment, and is associated with the genetic expansion of a CAG codon repeat encoding a polyglutamine-segment-containing protein called huntingtin. These Huntington’s disease mutations cause misfolding and aggregation of fragments of the mutant huntingtin protein, thereby likely contributing to disease toxicity through a combination of gain-of-toxic-function for the misfolded aggregates and a loss of function from sequestration of huntingtin and other proteins. As with other amyloid diseases, the mutant protein forms non-native fibrillar structures, which in Huntington’s disease are found within patients’ neurons. The intracellular deposits are associated with dysregulation of vital processes, and inter-neuronal transport of aggregates may contribute to disease progression. However, a molecular understanding of these aggregates and their detrimental effects has been frustrated by insufficient structural data on the misfolded protein state. In this review, we examine recent developments in the structural biology of polyglutamine-expanded huntingtin fragments, and especially the contributions enabled by advances in solid-state nuclear magnetic resonance spectroscopy. We summarize and discuss our current structural understanding of the huntingtin deposits and how this information furthers our understanding of the misfolding mechanism and disease toxicity mechanisms. Impact statement Many incurable neurodegenerative disorders are associated with, and potentially caused by, the amyloidogenic misfolding and aggregation of proteins. Usually, complex genetic and behavioral factors dictate disease risk and age of onset. Due to its principally mono-genic origin, which strongly predicts the age-of-onset by the extent of CAG repeat expansion, Huntington’s disease (HD) presents a unique opportunity to dissect the underlying disease-causing processes in molecular detail. Yet, until recently, the mutant huntingtin protein with its expanded polyglutamine domain has resisted structural study at the atomic level. We present here a review of recent developments in HD structural biology, facilitated by breakthrough data from solid-state NMR spectroscopy, electron microscopy, and complementary methods. The misfolded structures of the fibrillar proteins inform our mechanistic understanding of the disease-causing molecular processes in HD, other CAG repeat expansion disorders, and, more generally, protein deposition disease.

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