scholarly journals Defective linear and circular RNAs biogenesis in Huntington's disease: CAG repeat expansion hijacks neuronal splicing

2021 ◽  
Author(s):  
Dilara Ayyildiz ◽  
Alan Monziani ◽  
Takshashila Tripathi ◽  
Jessica Doering ◽  
Guendalina Bergonzoni ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Rna Binding ◽  
Neural Progenitors ◽  
Cag Repeat ◽  
Cag Repeats ◽  
Circular Rnas ◽  
In Vivo Models ◽  
Micro Rnas

Alternative splicing (AS) appears to be altered in Huntington's disease (HD), but its significance for early, pre-symptomatic disease stages has not been inspected. Here, taking advantage of Htt CAG knock-in mouse in vitro and in vivo models, we demonstrate a strong correlation between Htt CAG repeat length and increased aberrant linear AS, specifically affecting neural progenitors and, in vivo, the striatum prior to overt behavioral phenotypes stages. Remarkably, expanded Htt CAG repeats reflect on a previously neglected, global impairment of back-splicing, leading to decreased circular RNAs production in neural progenitors. Though the mechanisms of this dysregulation remain uncertain, our study unveils network of transcriptionally altered micro-RNAs and RNA-binding proteins (CELF, hnRNPS, PTBP, SRSF) which, in turn, might influence the AS machinery, primarily in neural cells. We suggest that this unbalanced expression of linear and circular RNAs might result in altered neural fitness, contributing to HD striatal vulnerability.

scholarly journals Lack of RAN-mediated toxicity in Huntington’s disease knock-in mice

2020 ◽  
Vol 117 (8) ◽  
pp. 4411-4417 ◽  
Author(s):  
Su Yang ◽  
Huiming Yang ◽  
Luoxiu Huang ◽  
Luxiao Chen ◽  
Zhaohui Qin ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Genome Editing ◽  
Mouse Models ◽  
Cag Repeat ◽  
Cag Repeats ◽  
Behavioral Phenotypes ◽  
Endogenous Level ◽  
Ran Translation

Identification of repeat-associated non-AUG (RAN) translation in trinucleotide (CAG) repeat diseases has led to the emerging concept that CAG repeat diseases are caused by nonpolyglutamine products. Nonetheless, the in vivo contribution of RAN translation to the pathogenesis of CAG repeat diseases remains elusive. Via CRISPR/Cas9-mediated genome editing, we established knock-in mouse models that harbor expanded CAG repeats in the mouse huntingtin gene to express RAN-translated products with or without polyglutamine peptides. We found that RAN translation is not detected in the knock-in mouse models when expanded CAG repeats are expressed at the endogenous level. Consistently, the expanded CAG repeats that cannot be translated into polyglutamine repeats do not yield the neuropathological and behavioral phenotypes that were found in knock-in mice expressing expanded polyglutamine repeats. Our findings suggest that RAN-translated products do not play a major role in the pathogenesis of CAG repeat diseases and underscore the importance in targeting polyglutamine repeats for therapeutics.

scholarly journals The MID1 Protein: A Promising Therapeutic Target in Huntington’s Disease

2021 ◽  
Vol 12 ◽  
Author(s):  
Annika Heinz ◽  
Judith Schilling ◽  
Willeke van Roon-Mom ◽  
Sybille Krauß
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Protein A ◽  
Cag Repeat ◽  
Cag Repeats ◽  
Progressive Movement ◽  
Promising Therapeutic Target ◽  
Promising Therapeutic Approach ◽  
Exon 1 ◽  
Polyglutamine Protein

Huntington’s disease (HD) is caused by an expansion mutation of a CAG repeat in exon 1 of the huntingtin (HTT) gene, that encodes an expanded polyglutamine tract in the HTT protein. HD is characterized by progressive psychiatric and cognitive symptoms associated with a progressive movement disorder. HTT is ubiquitously expressed, but the pathological changes caused by the mutation are most prominent in the central nervous system. Since the mutation was discovered, research has mainly focused on the mutant HTT protein. But what if the polyglutamine protein is not the only cause of the neurotoxicity? Recent studies show that the mutant RNA transcript is also involved in cellular dysfunction. Here we discuss the abnormal interaction of the mutant HTT transcript with a protein complex containing the MID1 protein. MID1 aberrantly binds to CAG repeats and this binding increases with CAG repeat length. Since MID1 is a translation regulator, association of the MID1 complex stimulates translation of mutant HTT mRNA, resulting in an overproduction of polyglutamine protein. Thus, blocking the interaction between MID1 and mutant HTT mRNA is a promising therapeutic approach. Additionally, we show that MID1 expression in the brain of both HD patients and HD mice is aberrantly increased. This finding further supports the concept of blocking the interaction between MID1 and mutant HTT mRNA to counteract mutant HTT translation as a valuable therapeutic strategy. In line, recent studies in which either compounds affecting the assembly of the MID1 complex or molecules targeting HTT RNA, show promising results.

scholarly journals Cerebral dopamine neurotrophic factor (CDNF) protects against quinolinic acid-induced toxicity in in vitro and in vivo models of Huntington’s disease

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
P. Stepanova ◽  
V. Srinivasan ◽  
D. Lindholm ◽  
M. H. Voutilainen
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Quinolinic Acid ◽  
Neurotrophic Factor ◽  
Striatal Neurons ◽  
In Vivo Models ◽  
Cerebral Dopamine Neurotrophic Factor ◽  
Cerebral Dopamine

Abstract Huntington’s disease (HD) is a neurodegenerative disorder with a progressive loss of medium spiny neurons in the striatum and aggregation of mutant huntingtin in the striatal and cortical neurons. Currently, there are no rational therapies for the treatment of the disease. Cerebral dopamine neurotrophic factor (CDNF) is an endoplasmic reticulum (ER) located protein with neurotrophic factor (NTF) properties, protecting and restoring the function of dopaminergic neurons in animal models of PD more effectively than other NTFs. CDNF is currently in phase I–II clinical trials on PD patients. Here we have studied whether CDNF has beneficial effects on striatal neurons in in vitro and in vivo models of HD. CDNF was able to protect striatal neurons from quinolinic acid (QA)-induced cell death in vitro via increasing the IRE1α/XBP1 signalling pathway in the ER. A single intrastriatal CDNF injection protected against the deleterious effects of QA in a rat model of HD. CDNF improved motor coordination and decreased ataxia in QA-toxin treated rats, and stimulated the neurogenesis by increasing doublecortin (DCX)-positive and NeuN-positive cells in the striatum. These results show that CDNF positively affects striatal neuron viability reduced by QA and signifies CDNF as a promising drug candidate for the treatment of HD.

scholarly journals The longevity-associated variant of BPIFB4 improves a CXCR4-mediated striatum–microglia crosstalk preventing disease progression in a mouse model of Huntington’s disease

2020 ◽  
Vol 11 (7) ◽  
Author(s):  
Alba Di Pardo ◽  
Elena Ciaglia ◽  
Monica Cattaneo ◽  
Anna Maciag ◽  
Francesco Montella ◽  
...  
Keyword(s):  
Mouse Model ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Neurodegenerative Disorder ◽  
Motor Dysfunction ◽  
Cag Repeats ◽  
Huntingtin Protein ◽  
Human Microglia

Abstract The longevity-associated variant (LAV) of the bactericidal/permeability-increasing fold-containing family B member 4 (BPIFB4) has been found significantly enriched in long-living individuals. Neuroinflammation is a key player in Huntington’s disease (HD), a neurodegenerative disorder caused by neural death due to expanded CAG repeats encoding a long polyglutamine tract in the huntingtin protein (Htt). Herein, we showed that striatal-derived cell lines with expanded Htt (STHdh Q111/111) expressed and secreted lower levels of BPIFB4, when compared with Htt expressing cells (STHdh Q7/7), which correlated with a defective stress response to proteasome inhibition. Overexpression of LAV-BPIFB4 in STHdh Q111/111 cells was able to rescue both the BPIFB4 secretory profile and the proliferative/survival response. According to a well-established immunomodulatory role of LAV-BPIFB4, conditioned media from LAV-BPIFB4-overexpressing STHdh Q111/111 cells were able to educate Immortalized Human Microglia—SV40 microglial cells. While STHdh Q111/111 dying cells were ineffective to induce a CD163 + IL-10high pro-resolving microglia compared to normal STHdh Q7/7, LAV-BPIFB4 transduction promptly restored the central immune control through a mechanism involving the stromal cell-derived factor-1. In line with the in vitro results, adeno-associated viral-mediated administration of LAV-BPIFB4 exerted a CXCR4-dependent neuroprotective action in vivo in the R6/2 HD mouse model by preventing important hallmarks of the disease including motor dysfunction, body weight loss, and mutant huntingtin protein aggregation. In this view, LAV-BPIFB4, due to its pleiotropic ability in both immune compartment and cellular homeostasis, may represent a candidate for developing new treatment for HD.

scholarly journals Predicting Disease Onset from Mutation Status Using Proband and Relative Data with Applications to Huntington's Disease

2012 ◽  
Vol 2012 ◽  
pp. 1-19 ◽  
Author(s):  
Tianle Chen ◽  
Yuanjia Wang ◽  
Yanyuan Ma ◽  
Karen Marder ◽  
Douglas R. Langbehn
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Family Member ◽  
Disease Onset ◽  
Repeat Length ◽  
Cag Repeat ◽  
Cag Repeats ◽  
Observational Research ◽  
Accurate Estimation ◽  
Combined Data

Huntington's disease (HD) is a progressive neurodegenerative disorder caused by an expansion of CAG repeats in the IT15 gene. The age-at-onset (AAO) of HD is inversely related to the CAG repeat length and the minimum length thought to cause HD is 36. Accurate estimation of the AAO distribution based on CAG repeat length is important for genetic counseling and the design of clinical trials. In the Cooperative Huntington's Observational Research Trial (COHORT) study, the CAG repeat length is known for the proband participants. However, whether a family member shares the huntingtin gene status (CAG expanded or not) with the proband is unknown. In this work, we use the expectation-maximization (EM) algorithm to handle the missing huntingtin gene information in first-degree family members in COHORT, assuming that a family member has the same CAG length as the proband if the family member carries a huntingtin gene mutation. We perform simulation studies to examine performance of the proposed method and apply the methods to analyze COHORT proband and family combined data. Our analyses reveal that the estimated cumulative risk of HD symptom onset obtained from the combined data is slightly lower than the risk estimated from the proband data alone.

scholarly journals Parkinsonism with a Hint of Huntington’s from 29 CAG Repeats in HTT

2019 ◽  
Vol 9 (10) ◽  
pp. 245
Author(s):  
Sipilä JOT
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Clinical Phenotype ◽  
Cag Repeat ◽  
Cag Repeats ◽  
Test Results ◽  
Intermediate Allele ◽  
History Of ◽  
Neurophysiological Test ◽  
History Of Parkinson’S Disease

Huntington’s disease is caused by at least 36 cytosine-adenine-guanine (CAG) repeats in an HTT gene allele, but repeat tracts in the intermediate range (27–35 repeats) also display a subtle phenotype. This patient had a slightly elongated CAG repeat tract (29 repeats), a prominent family history of Parkinson’s disease (PD), and a clinical phenotype mostly consistent with PD, but early dystonia and poor levodopa response. Neurophysiological test results were more consistent with Huntington’s disease (HD) than PD. It is suggested that the intermediate allele modulated the clinical phenotype of PD in this patient.

scholarly journals The timing and impact of psychiatric, cognitive and motor abnormalities in Huntington's disease

2020 ◽  
Author(s):  
Branduff McAllister ◽  
James F. Gusella ◽  
G. Bernhard Landwehrmeyer ◽  
Jong-Min Lee ◽  
Marcy E. MacDonald ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Clinical Characteristics ◽  
Negative Impact ◽  
Cag Repeat ◽  
Cag Repeats ◽  
Motor Symptoms ◽  
Cognitive Symptoms ◽  
Cognitive Symptom ◽  
Motor Abnormalities

Objective: To assess the prevalence, timing and functional impact of psychiatric, cognitive and motor abnormalities in Huntington's disease (HD), we analysed retrospective clinical data from individuals with manifest HD. Methods: Clinical features of HD patients were analysed for 6316 individuals in the European REGISTRY study from 161 sites across 17 countries. Data came from clinical history and the Clinical Characteristics Questionnaire that assessed eight symptoms: motor, cognitive, apathy, depression, perseverative/obsessive behavior, irritability, violent/aggressive behavior, and psychosis. Multiple logistic regression was used to analyse relationships between symptoms and functional outcomes. Results: The initial manifestation of HD is increasingly likely to be motor, and less likely to be psychiatric, as age at presentation increases. The nature of the first manifestation is not associated with pathogenic CAG repeat length. Symptom prevalence data from the patient-completed Clinical Characteristics Questionnaire correlate specifically with validated clinical measures. Using these data, we show that psychiatric and cognitive symptoms are common in HD, with earlier onsets associated with longer CAG repeats. 42.4% of HD patients reported at least one psychiatric or cognitive symptom before motor symptoms, with depression most common. Apathy and cognitive impairment tend to come later in the disease course. Each psychiatric or cognitive symptom was associated with significantly reduced total functional capacity scores. Conclusions: Psychiatric and cognitive symptoms occur before motor symptoms in many more HD patients than previously reported. They have a greater negative impact on daily life than involuntary movements and should be specifically targeted with clinical outcome measures and treatments.

scholarly journals Genomic architecture differences at the HTT locus associated with symptomatic and pre-symptomatic cases of Huntington’s disease in a pilot study

2021 ◽  
pp. 1-6
Author(s):  
Matthew Salter ◽  
Ryan Powell ◽  
Jennifer Back ◽  
Francis Grand ◽  
Christina Koutsothanasi ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Clinical Symptoms ◽  
Disease Onset ◽  
Cag Repeat ◽  
Cag Repeats ◽  
Healthy Controls ◽  
Chromosome Conformation ◽  
Chromatin Architecture ◽  
Patient Groups

Huntington’s Disease (HD) is a progressive neurodegenerative condition that causes degeneration of neurons in the brain, ultimately leading to death. The root cause of HD is an expanded trinucleotide Cytosine-Adenine-Guanine (CAG) repeat in the “huntingtin gene” (HTT). While there is a rough correlation between the number of CAG repeats and disease onset, the development of clinical symptoms can vary by decades within individuals and little is known about this presymptomatic phase. Using peripheral blood samples from HD patients and healthy controls we used EpiSwitch®, a validated high-resolution industrial platform for the detection of chromosome conformations, to assess chromatin architecture in the immediate vicinity of the HTT gene. We evaluated chromatin conformations at 20 sites across 225 kb of the HTT locus in a small cohort of healthy controls, verified symptomatic HD patients (CAG, n>39) and patients with CAG expansions who had not yet manifested clinical symptoms of HD. Discrete chromosome conformations were observed across the patient groups. We found two constitutive interactions (occurring in all patient groups) and seven conditional interactions which were present in HD, but not in healthy controls. Most important, we observed three conditional interactions that were present only in HD patients manifesting clinical symptoms (symptomatic cases), but not in presymptomatic cases. 85% (6 out of 7) of the patients in the symptomatic HD cohort demonstrated at least one of the specific chromosome conformations associated with symptomatic HD. Our results provide the first evidence that chromatin architecture at the HTT locus is systemically altered in patients with HD, with conditional differences between clinical stages. Given the high clinical need in having a molecular tool to assess disease progression in HD, these results strongly suggest that the non-invasive assessment of Chromosome Conformation Signatures (CCS) warrant further study as a prognostic tool in HD.

scholarly journals Genomic architecture differences at the HTT locus underlie symptomatic and pre-symptomatic cases of Huntington’s disease.

F1000Research ◽  
2019 ◽  
Vol 7 ◽  
pp. 1757
Author(s):  
Matthew Salter ◽  
Ryan Powell ◽  
Jennifer Back ◽  
Francis Grand ◽  
Christina Koutsothanasi ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Clinical Symptoms ◽  
Disease Onset ◽  
Cag Repeat ◽  
Cag Repeats ◽  
Healthy Controls ◽  
Chromosome Conformation ◽  
Chromatin Architecture ◽  
Patient Groups

Background:Huntington’s disease (HD) is a progressive neurodegenerative condition that causes degeneration of neurons in the brain, ultimately leading to death. The root cause of HD is an expanded trinucleotide cytosine-adenine-guanine (CAG) repeat in the “huntingtin gene” (HTT). While there is a rough correlation between the number of CAG repeats and disease onset, the development of clinical symptoms can vary by decades within individuals and little is known about this pre-symptomatic phase.Methods:Using peripheral blood samples from HD patients and healthy controls we usedEpiSwitch™, a validated high-resolution industrial platform for the detection of chromosome conformations, to assess chromatin architecture in the immediate vicinity of theHTTgene. We evaluated chromatin conformations at 20 sites across 225 kb of theHTTlocus in healthy controls, verified symptomatic HD patients (CAG, n>39) and patients with CAG expansions who had not yet manifested clinical symptoms of HD.Results:Discrete chromosome conformations were observed across the patient groups. We found two constitutive interactions (occurring in all patient groups) and seven conditional interactions which were present in HD, but not in healthy controls. Most important, we observed three conditional interactions that were present only in HD patients manifesting clinical symptoms (symptomatic cases), but not in presymptomatic cases. Of the patients in the symptomatic HD cohort, 86% (6 out of 7) demonstrated at least one of the specific chromosome conformations associated with symptomatic HD.Conclusion:Our results provide the first evidence that chromatin architecture at theHTTlocus is systemically altered in patients with HD, with conditional differences between clinical stages. Given the high clinical need in having a molecular tool to assess disease progression in HD, these results strongly suggest that the non-invasive assessment of chromosome conformation signatures can be a valuable addition to prognostic assessment of HD patients.

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