scholarly journals Purinergic Signaling in the Pathophysiology and Treatment of Huntington’s Disease

2021 ◽  
Vol 15 ◽  
Author(s):  
Melissa Talita Wiprich ◽  
Carla Denise Bonan
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Neurodegenerative Disorder ◽  
Early Stage ◽  
Purinergic Signaling ◽  
Neuronal Loss ◽  
Movement Control ◽  
Motor Dysfunction ◽  
Purine Nucleotides ◽  
Psychiatric Disturbance

Huntington’s disease (HD) is a devastating, progressive, and fatal neurodegenerative disorder inherited in an autosomal dominant manner. This condition is characterized by motor dysfunction (chorea in the early stage, followed by bradykinesia, dystonia, and motor incoordination in the late stage), psychiatric disturbance, and cognitive decline. The neuropathological hallmark of HD is the pronounced neuronal loss in the striatum (caudate nucleus and putamen). The striatum is related to the movement control, flexibility, motivation, and learning and the purinergic signaling has an important role in the control of these events. Purinergic signaling involves the actions of purine nucleotides and nucleosides through the activation of P2 and P1 receptors, respectively. Extracellular nucleotide and nucleoside-metabolizing enzymes control the levels of these messengers, modulating the purinergic signaling. The striatum has a high expression of adenosine A2A receptors, which are involved in the neurodegeneration observed in HD. The P2X7 and P2Y2 receptors may also play a role in the pathophysiology of HD. Interestingly, nucleotide and nucleoside levels may be altered in HD animal models and humans with HD. This review presents several studies describing the relationship between purinergic signaling and HD, as well as the use of purinoceptors as pharmacological targets and biomarkers for this neurodegenerative disorder.

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 Fiberoptic endoscopic evaluation of swallowing in early-to-advanced stage Huntington’s disease

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Antonio Schindler ◽  
Nicole Pizzorni ◽  
Jenny Sassone ◽  
Lorenzo Nanetti ◽  
Anna Castaldo ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Neurodegenerative Disorder ◽  
Early Stage ◽  
Clinical Care ◽  
Self Report ◽  
Advanced Stage ◽  
Endoscopic Evaluation ◽  
Silent Aspiration ◽  
Scale Scores

Abstract Huntington's disease (HD) is a neurodegenerative disorder characterized by motor disturbances, cognitive decline, and behaviour changes. A well-recognized feature of advanced HD is dysphagia, which leads to malnutrition and aspiration pneumonia, the latter being the primary cause of death in HD. Previous studies have underscored the importance of dysphagia in HD patients with moderate-to-advanced stage disease, but it is unclear whether dysphagia affects patients already at an early stage of disease and whether genetic or clinical factors can predict its severity. We performed fiberoptic endoscopic evaluation of swallowing (FEES) in 61 patients with various stages of HD. Dysphagia was found in 35% of early-stage, 94% of moderate-stage, and 100% of advanced-stage HD. Silent aspiration was found in 7.7% of early-stage, 11.8% of moderate-stage, and 27.8% of advanced-stage HD. A strong correlation was observed between disease progression and dysphagia severity: worse dysphagia was associated with worsening of motor symptoms. Dysphagia severity as assessed by FEES correlated with Huntington’s Disease Dysphagia Scale scores (a self-report questionnaire specific for evaluating swallowing in HD). The present findings add to our understanding of dysphagia onset and progression in HD. A better understanding of dysphagia onset and progression in HD may inform guidelines for standard clinical care in dysphagia, its recognition, and management.

Predictors of Working Capacity Changes Related to Huntington’s Disease: A Longitudinal Study

2021 ◽  
pp. 1-8
Author(s):  
Kasper F. van der Zwaan ◽  
Milou Jacobs ◽  
Erik W. van Zwet ◽  
Raymund A.C. Roos ◽  
Susanne T. de Bot
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Neurodegenerative Disorder ◽  
Psychiatric Symptoms ◽  
Motor Dysfunction ◽  
Healthy Controls ◽  
Working Capacity ◽  
Predictive Values ◽  
Gene Carriers ◽  
The Impact

Background: Huntington’s disease (HD) is an inherited neurodegenerative disorder that is characterized by motor, cognitive, and psychiatric symptoms. Although 65%of HD expanded gene carriers report changes in employment as the first functional loss, little is known about the predictors leading to changes of working capacity. Given the impact on quality of life, understanding of these factors is of great clinical value. Objective: This study evaluates disease specific characteristics and their predictive value in loss of working capacity in HD. Methods: Longitudinal data was collected through the worldwide observational study (Enroll-HD), with 15,301 participants in total and 2,791 HD and healthy control participants meeting the inclusion criteria. Changes in working capacity were analyzed by means of a survival analysis. Predictive values of demographic factors and clinical characteristics were assessed for premanifest and manifest HD through Cox regressions. Results: HD expanded gene carriers, manifest and premanifest combined, had a 31%chance of experiencing changes in employment after three years, compared to 4%in healthy controls. Apathy was found to be the most crucial determinant of working capacity changes in premanifest HD, while executive and motor dysfunction play an important role in manifest HD. Conclusion: HD expanded gene carriers are more likely to lose working capacity compared to healthy controls. Disease progression, altered motor function, cognitive decline, and in an early stage of the disease apathetic symptoms are indicative of negative changes in working capacity. Clinicians should recognize that early disease related changes, especially apathy, can affect working capacity.

scholarly journals SorCS2 dynamically interacts with TrkB and GluN2B to control neurotransmission and Huntington's disease progression

2021 ◽  
Author(s):  
Alena Salašová ◽  
Niels Sanderhoff Degn ◽  
Mikhail Paveliev ◽  
Niels Kjaergaard Madsen ◽  
Saray Benito ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Disease Progression ◽  
Neurodegenerative Disorder ◽  
Dorsal Striatum ◽  
Long Term Potentiation ◽  
Motor Dysfunction ◽  
Motor Deficits ◽  
Bdnf Expression ◽  
Term Potentiation

Huntington's disease (HD) is a fatal neurodegenerative disorder characterized by progressive motor dysfunction and loss of medium spiny neurons (MSNs) in dorsal striatum. Brain-derived neurotrophic factor (BDNF) sustains functionality and integrity of MSNs, and thus reduced BDNF signaling is integral to the disease. Here we show that SorCS2 is expressed in MSNs with reduced expression in R6/1 HD model, and that SorCS2 deficiency exacerbates the disease progression in R6/1 mice. Furthermore, we find that SorCS2 binds TrkB and the NMDA receptor subunit GluN2B, which is required to control neurotransmission in corticostriatal synapses. While BDNF stimulates SorCS2-TrkB complex formation to enable TrkB signaling, it disengages SorCS2 from GluN2B, leading to enrichment of the subunit at postsynaptic densities. Consequently, long-term potentiation (LTP) is abolished in SorCS2 deficient mice, despite increased striatal TrkB and unaltered BDNF expression. In contrast, the addition of exogenous BDNF rescues the phenotype. Finally, GluN2B, but not GluN2A, currents are also severely impaired in the SorCS2 KO mice. To conclude, we uncovered that SorCS2 dynamically targets TrkB and GluN2B to orchestrate BDNF-dependent plasticity in MSNs of dorsal striatum. We propose that SorCS2 deficiency impairs MSN function thereby increasing neuronal vulnerability and accelerating the motor deficits in Huntington's disease.

scholarly journals Implicit Contextual Learning in Prodromal and Early Stage Huntington's Disease Patients

2012 ◽  
Vol 18 (4) ◽  
pp. 689-696 ◽  
Author(s):  
Marieke van Asselen ◽  
Inês Almeida ◽  
Filipa Júlio ◽  
Cristina Januário ◽  
Elzbieta Bobrowicz Campos ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Implicit Learning ◽  
Neurodegenerative Disorder ◽  
Response Selection ◽  
Early Stage ◽  
Contextual Information ◽  
Learning Task ◽  
Contextual Learning ◽  
Control Subjects

AbstractHuntington's disease (HD) is a genetic neurodegenerative disorder affecting the basal ganglia. These subcortical structures are particularly important for motor functions, response selection and implicit learning. In the current study, we have assessed prodromal and symptomatic HD participants with an implicit contextual learning task that is not based on motor learning, but on a purely visual implicit learning mechanism. We used an implicit contextual learning task in which subjects need to locate a target among several distractors. In half of the trials, the positions of the distractors and target stimuli were repeated. By memorizing this contextual information, attention can be guided faster to the target stimulus. Nine symptomatic HD participants, 16 prodromal HD participants and 22 control subjects were included. We found that the responses of the control subjects were faster for the repeated trials than for the new trials, indicating that their visual search was facilitated when repeated contextual information was present. In contrast, no difference in response times between the repeated and new trials was found for the symptomatic and prodromal HD participants. The results of the current study indicate that both prodromal and symptomatic HD participants are impaired on an implicit contextual learning task. (JINS, 2012, 18, 1–8)

scholarly journals Neuroimmunology of Huntington’s Disease: Revisiting Evidence from Human Studies

2016 ◽  
Vol 2016 ◽  
pp. 1-10 ◽  
Author(s):  
Natalia P. Rocha ◽  
Fabiola M. Ribeiro ◽  
Erin Furr-Stimming ◽  
Antonio L. Teixeira
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Neurodegenerative Disorder ◽  
Genetic Disorder ◽  
Cag Repeat ◽  
Motor Dysfunction ◽  
Gene Encoding ◽  
Ultimate Cause ◽  
The Central Nervous System ◽  
Inflammatory Changes

Huntington’s disease (HD) is a neurodegenerative disorder characterized by selective loss of neurons in the striatum and cortex, which leads to progressive motor dysfunction, cognitive decline, and psychiatric disorders. Although the cause of HD is well described—HD is a genetic disorder caused by a trinucleotide (CAG) repeat expansion in the gene encoding for huntingtin (HTT) on chromosome 4p16.3—the ultimate cause of neuronal death is still uncertain. Apart from impairment in systems for handling abnormal proteins, other metabolic pathways and mechanisms might contribute to neurodegeneration and progression of HD. Among these, inflammation seems to play a role in HD pathogenesis. The current review summarizes the available evidence about immune and/or inflammatory changes in HD. HD is associated with increased inflammatory mediators in both the central nervous system and periphery. Accordingly, there have been some attempts to slow HD progression targeting the immune system.

scholarly journals Cognitive Deficits in the R6/2 mouse model of Huntington’s disease and their Amelioration with Donepezil

2014 ◽  
Vol 27 (3) ◽  
Author(s):  
Carol A. Murphy ◽  
Neil E. Paterson ◽  
Angela Chen ◽  
Washington Arias ◽  
Dansha He ◽  
...  
Keyword(s):  
Mouse Model ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Neurodegenerative Disorder ◽  
Psychiatric Symptoms ◽  
Motor Dysfunction ◽  
Cag Repeats ◽  
Motor Deficits ◽  
Cholinergic Function ◽  
Severe Motor

The neurodegenerative disorder Huntington’s disease (HD) is characterized by motor dysfunction, cognitive impairment and psychiatric symptoms. The R6/2 (120 CAG repeats) mouse model of HD recapitulates many of the symptoms of the disease, including marked impairments in cognition and severe motor deficits. As cholinergic function has been reported to be affected in both HD patients and this mouse model, we tested whether treatment with the cholinesterase inhibitor donepezil could improve the R6/2 mice performance in the two-choice swim tank visual discrimination and reversal task. In this test mice are trained to swim towards a light cued platform located on one side of a water-filled tank. Once mice reach an acquisition criterion a reversal ensues. Wild-type and R6/2 mice were dosed with donepezil (0.6 mg/kg/day) or vehicle starting at 8 weeks of age and tested starting at 9 weeks of age. In experiment 1, vehicle-treated R6/2 mice showed a significant deficit during acquisition and reversal as compared to vehicle-treated WT mice. Donepezil improved reversal in the R6/2 group. In experiment 2, we confirmed the beneficial effect of donepezil on reversal in similar conditions. Donepezil had no effect on activity as measured in the open field test or through the latency to reach the platform during the swim test. We suggest that the donepezil-induced improvements in cognitive function observed in the R6/2 transgenic model of HD may reflect amelioration of deficits in cholinergic function that have been reported previously in this model. Further work is required to confirm the findings of these interesting although preliminary studies.

scholarly journals Retrospective Analysis of Healthcare Resource Use, Treatment Patterns, and Treatment-related Events in Patients with Huntington’s Disease–associated Chorea Initiated on Tetrabenazine

10.36469/9779 ◽  
2018 ◽  
Vol 6 (1) ◽  
pp. 15-24
Author(s):  
Victor W. Sung ◽  
Sanjay K. Gandhi ◽  
Victor Abler ◽  
Brian Davis ◽  
Debra E. Irwin ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Median Time ◽  
Index Date ◽  
Neurodegenerative Disorder ◽  
Psychiatric Disturbance ◽  
Treatment Persistence ◽  
Before And After ◽  
Median Daily Dose

Background: Huntington’s disease (HD) is a multifaceted neurodegenerative disorder characterized by involuntary movements, specifically chorea, as well as behavioral and psychiatric disturbance, and cognitive dysfunction. Tetrabenazine was the first approved treatment for chorea, although tolerability concerns exist. Objectives: To characterize demographic and clinical characteristics of HD patients with chorea based on tetrabenazine use and examine treatment persistence with tetrabenazine in a real-world setting. Methods: Patients with a claim for HD-associated chorea (ICD-9-CM code 333.4) between 1/1/08 and 9/30/15 were selected from the MarketScan® Commercial and Medicare Supplemental databases. The first diagnosis date during the study period was considered the index date, with ≥6 months of continuous medical and prescription coverage before and after the index date. Treatment persistence was defined as the number of days from initiation to discontinuation or end of follow-up period. Discontinuation was defined as a gap in therapy of ≥60 days. Results: 1644 patients met selection criteria (mean age ± standard deviation: 54.5 ± 15.5), of which 151 (9.2%) were treated with tetrabenazine during the study period. The average (median) daily dose of tetrabenazine during the treatment period was 45.5 (42.3) mg/day. A total of 41.8% (59/141) of HD patients who initiated tetrabenazine experienced a ≥60-day gap in tetrabenazine therapy, with a median time to discontinuation of 293.5 days. During the 6-month post-index period after HD diagnosis, HD patients incurred higher all-cause healthcare costs ($20 204) vs the 6-month pre-index period ($6057), driven by higher hospitalization and pharmacy costs. Conclusions:A small percentage of HD patients with chorea were treated with tetrabenazine and discontinuation rates were high among those receiving treatment, with a median time to discontinuation of 9 months.

scholarly journals Purine Nucleotides Metabolism and Signaling in Huntington’s Disease: Search for a Target for Novel Therapies

2021 ◽  
Vol 22 (12) ◽  
pp. 6545
Author(s):  
Marta Tomczyk ◽  
Talita Glaser ◽  
Ewa M. Slominska ◽  
Henning Ulrich ◽  
Ryszard T. Smolenski
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Purinergic Receptor ◽  
Purinergic Signaling ◽  
Nucleotide Metabolism ◽  
Cag Repeats ◽  
Purine Nucleotides ◽  
Atp Pool ◽  
Exon 1 ◽  
System Disorder

Huntington’s disease (HD) is a multi-system disorder that is caused by expanded CAG repeats within the exon-1 of the huntingtin (HTT) gene that translate to the polyglutamine stretch in the HTT protein. HTT interacts with the proteins involved in gene transcription, endocytosis, and metabolism. HTT may also directly or indirectly affect purine metabolism and signaling. We aimed to review existing data and discuss the modulation of the purinergic system as a new therapeutic target in HD. Impaired intracellular nucleotide metabolism in the HD affected system (CNS, skeletal muscle and heart) may lead to extracellular accumulation of purine metabolites, its unusual catabolism, and modulation of purinergic signaling. The mechanisms of observed changes might be different in affected systems. Based on collected findings, compounds leading to purine and ATP pool reconstruction as well as purinergic receptor activity modulators, i.e., P2X7 receptor antagonists, may be applied for HD treatment.

scholarly journals Epigenomic Remodeling in Huntington’s Disease—Master or Servant?

Epigenomes ◽  
2020 ◽  
Vol 4 (3) ◽  
pp. 15
Author(s):  
Geraldine Zimmer-Bensch
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Neurodegenerative Disorder ◽  
Genetic Defect ◽  
Neuronal Loss ◽  
Histone Variants ◽  
Therapeutic Concepts ◽  
Exon 1 ◽  
Epigenetic Signatures ◽  
Neuronal Physiology

In light of our aging population, neurodegenerative disorders are becoming a tremendous challenge, that modern societies have to face. They represent incurable, progressive conditions with diverse and complex pathological features, followed by catastrophic occurrences of massive neuronal loss at the later stages of the diseases. Some of these disorders, like Huntington’s disease (HD), rely on defined genetic factors. HD, as an incurable, fatal hereditary neurodegenerative disorder characterized by its mid-life onset, is caused by the expansion of CAG trinucleotide repeats coding for glutamine (Q) in exon 1 of the huntingtin gene. Apart from the genetic defect, environmental factors are thought to influence the risk, onset and progression of HD. As epigenetic mechanisms are known to readily respond to environmental stimuli, they are proposed to play a key role in HD pathogenesis. Indeed, dynamic epigenomic remodeling is observed in HD patients and in brains of HD animal models. Epigenetic signatures, such as DNA methylation, histone variants and modifications, are known to influence gene expression and to orchestrate various aspects of neuronal physiology. Hence, deciphering their implication in HD pathogenesis might open up new paths for novel therapeutic concepts, which are discussed in this review.

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