scholarly journals The Therapeutic Potential of Neuronal K-Cl Co-Transporter KCC2 in Huntington’s Disease and Its Comorbidities

2020 ◽  
Vol 21 (23) ◽  
pp. 9142
Author(s):  
Katie Andrews ◽  
Sunday Solomon Josiah ◽  
Jinwei Zhang
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Protein Interactions ◽  
Therapeutic Target ◽  
Neuronal Excitability ◽  
Therapeutic Potential ◽  
Genetic Disorder ◽  
Clinical Manifestations ◽  
Cognitive Change ◽  
The Brain

Intracellular chloride levels in the brain are regulated primarily through the opposing effects of two cation-chloride co-transporters (CCCs), namely K+-Cl− co-transporter-2 (KCC2) and Na+-K+-Cl− co-transporter-1 (NKCC1). These CCCs are differentially expressed throughout the course of development, thereby determining the excitatory-to-inhibitory γ-aminobutyric acid (GABA) switch. GABAergic excitation (depolarisation) is important in controlling the healthy development of the nervous system; as the brain matures, GABAergic inhibition (hyperpolarisation) prevails. This developmental switch in excitability is important, as uncontrolled regulation of neuronal excitability can have implications for health. Huntington’s disease (HD) is an example of a genetic disorder whereby the expression levels of KCC2 are abnormal due to mutant protein interactions. Although HD is primarily considered a motor disease, many other clinical manifestations exist; these often present in advance of any movement abnormalities. Cognitive change, in addition to sleep disorders, is prevalent in the HD population; the effect of uncontrolled KCC2 function on cognition and sleep has also been explored. Several mechanisms by which KCC2 expression is reduced have been proposed recently, thereby suggesting extensive investigation of KCC2 as a possible therapeutic target for the development of pharmacological compounds that can effectively treat HD co-morbidities. Hence, this review summarizes the role of KCC2 in the healthy and HD brain, and highlights recent advances that attest to KCC2 as a strong research and therapeutic target candidate.

Neuroinflammation in Huntington’s disease: A starring role for astrocyte and microglia

2021 ◽  
Vol 19 ◽  
Author(s):  
Julieta Saba ◽  
Federico López Couselo ◽  
Julieta Bruno ◽  
Lila Carniglia ◽  
Daniela Durand ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Genetic Disorder ◽  
Cag Repeat ◽  
Inflammatory Factors ◽  
Therapeutic Approaches ◽  
Reactive Microglia ◽  
New Treatments ◽  
The Brain

: Huntington’s disease (HD) is a neurodegenerative genetic disorder caused by a CAG repeat expansion in the huntingtin gene. HD causes motor, cognitive, and behavioral dysfunction. Since no existing treatment affects the course of this disease, new treatments are needed. Inflammation is frequently observed in HD patients before symptom onset. Neuroinflammation, characterized by the presence of reactive microglia and astrocytes and inflammatory factors within the brain, is also detected early. However, in comparison with other neurodegenerative diseases, the role of neuroinflammation in HD is much less known. Work has been dedicated to altered microglial and astrocytic functions in the context of HD, but less attention has been given to glial participation in neuroinflammation. This review describes evidence of inflammation in HD patients and animal models. It also discusses recent knowledge on neuroinflammation in HD, highlighting astrocyte and microglia involvement in the disease and considering anti-inflammatory therapeutic approaches.

Hypothesis: huntingtin may function in membrane association and vesicular traffickingThis paper is one of a selection of papers published in this Special Issue, entitled CSBMCB — Membrane Proteins in Health and Disease.

2006 ◽  
Vol 84 (6) ◽  
pp. 912-917 ◽  
Author(s):  
Ray Truant ◽  
Randy Atwal ◽  
Anjee Burtnik
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Protein Interactions ◽  
Cell Biology ◽  
Genetic Disorder ◽  
Scaffolding Protein ◽  
Membrane Association ◽  
Protein Protein Interactions ◽  
Polyglutamine Expansion ◽  
Exact Function

Huntington’s disease is a progressive neurodegenerative genetic disorder that is caused by a CAG triplet-repeat expansion in the first exon of the IT15 gene. This CAG expansion results in polyglutamine expansion in the 350 kDa huntingtin protein. The exact function of huntingtin is unknown. Understanding the pathological triggers of mutant huntingtin, and distinguishing the cause of disease from downstream effects, is critical to designing therapeutic strategies and defining long- and short-term goals of therapy. Many studies that have sought to determine the functions of huntingtin by determining huntingtin’s protein–protein interactions have been published. Through these studies, huntingtin has been seen to interact with a large number of proteins, and is likely a scaffolding protein for protein–protein interactions. Recently, using imaging, integrative proteomics, and cell biology, huntingtin has been defined as a membrane-associated protein, with activities related to axonal trafficking of vesicles and mitochondria. These functions have also been attributed to some huntingtin-interacting proteins. Additionally, discoveries of a membrane association domain and a palmitoylation site in huntingtin reinforce the fact that huntingtin is membrane associated. In Huntington’s disease mouse and fly models, axonal vesicle trafficking is inhibited, and lack of proper uptake of neurotrophic factors may be an important pathological trigger leading to striatal cell death in Huntington’s disease. Here we discuss recent advances from many independent groups and methodologies that are starting to resolve the elusive function of huntingtin in vesicle transport, and evidence that suggests that huntingtin may be directly involved in membrane interactions.

scholarly journals Apathy Is Related to Cognitive Control and Striatum Volumes in Prodromal Huntington’s Disease

2019 ◽  
Vol 25 (05) ◽  
pp. 462-469 ◽  
Author(s):  
Maria B. Misiura ◽  
Jennifer Ciarochi ◽  
Jatin Vaidya ◽  
Jeremy Bockholt ◽  
Hans J. Johnson ◽  
...  
Keyword(s):  
Cognitive Control ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Genetic Disorder ◽  
Motor Impairment ◽  
Motor Symptom ◽  
Direct Result ◽  
Outcome Variable ◽  
Preclinical Phase ◽  
The Brain

AbstractObjectives: Apathy is a debilitating symptom of Huntington’s disease (HD) and manifests before motor diagnosis, making it an excellent therapeutic target in the preclinical phase of Huntington’s disease (prHD). HD is a neurological genetic disorder characterized by cognitive and motor impairment, and psychiatric abnormalities. Apathy is not well characterized within the prHD. In previous literature, damage to the caudate and putamen has been correlated with increased apathy in other neurodegenerative and movement disorders. The objective of this study was to determine whether apathy severity in individuals with prHD is related to striatum volumes and cognitive control. We hypothesized that, within prHD individuals, striatum volumes and cognitive control scores would be related to apathy. Methods: We constructed linear mixed models to analyze striatum volumes and cognitive control, a composite measure that includes tasks assessing with apathy scores from 797 prHD participants. The outcome variable for each model was apathy, and the independent variables for the four separate models were caudate volume, putamen volume, cognitive control score, and motor symptom score. We also included depression as a covariate to ensure that our results were not solely related to mood. Results: Caudate and putamen volumes, as well as measures of cognitive control, were significantly related to apathy scores even after controlling for depression. Conclusions: The behavioral apathy expressed by these individuals was related to regions of the brain commonly associated with isolated apathy, and not a direct result of mood symptoms. (JINS, 2019, 25, 462–469)

scholarly journals Proteasome impairment does not contribute to pathogenesis in R6/2 Huntington's disease mice: exclusion of proteasome activator REGγ as a therapeutic target

2006 ◽  
Vol 15 (4) ◽  
pp. 665-665 ◽  
Author(s):  
John S. Bett ◽  
Geoffrey M. Goellner ◽  
Ben Woodman ◽  
Gregory Pratt ◽  
Martin Rechsteiner ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Therapeutic Target ◽  
Proteasome Activator

Huntington’s Disease in Israel: A Population-based Study Using 20 Years of Routinely-Collected Healthcare Data

2021 ◽  
pp. 1-9
Author(s):  
Natalie Gavrielov-Yusim ◽  
Yael Barer ◽  
Michael Martinec ◽  
Athanasios Siadimas ◽  
Spyros Roumpanis ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Healthcare Utilization ◽  
Behavioral Problems ◽  
Clinical Manifestations ◽  
Population Based ◽  
Emergency Department Visits ◽  
Study Cohort ◽  
Population Based Study ◽  
Healthcare Data

Background: Huntington’s disease (HD) is a rare, genetic, neurodegenerative disease. Obtaining population-level data on epidemiology and disease management is challenging. Objective: To investigate the epidemiology, clinical manifestations, treatment, and healthcare utilization of patients with HD in Israel. Methods: Retrospective population-based cohort study, including 20 years of routinely collected data from Maccabi Healthcare Services, an insurer and healthcare provider for one-quarter of the Israeli population. Results: The study cohort included 109 adult patients (aged ≥18 years) diagnosed with HD, with mean age of 49.9 years and 56%females. The most common HD-related conditions were anxiety (40%), behavioral problems (34%), sleep disorders (21%), and falls (13%). Annual incidence rates for HD ranged from 0.17 to 1.34 per 100,000 from 2000 to 2018; the 2018 crude prevalence in adults was 4.36 per 100,000. Median survival from diagnosis was approximately 12 years (95%CI: 10.4–15.3). The most frequent symptomatic treatments were antidepressants (69%), antipsychotics (63%), and tetrabenazine (63%), the only drug approved for the treatment of HD chorea in Israel during the examined period. Patterns of healthcare utilization changed as disease duration increased, reflected by increased frequency of emergency department visits and home visits. Conclusion: This retrospective population-based study provides insights into the prevalence, incidence, clinical profile, survival, and resource utilization of patients with HD in ethnically diverse Israel. The findings in this study are generally consistent with the international literature and demonstrate the value of routinely collected healthcare data as a complementary resource in HD research.

scholarly journals Huntington's Disease: An Immune Perspective

2011 ◽  
Vol 2011 ◽  
pp. 1-7 ◽  
Author(s):  
Annapurna Nayak ◽  
Rafia Ansar ◽  
Sunil K. Verma ◽  
Domenico Marco Bonifati ◽  
Uday Kishore
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Neurodegenerative Disorder ◽  
Typical Feature ◽  
Trinucleotide Repeats ◽  
Mutant Huntingtin Protein ◽  
Unexplored Area ◽  
Cag Trinucleotide Repeats ◽  
The Brain ◽  
Abnormal Expansion

Huntington's disease (HD) is a progressive neurodegenerative disorder that is caused by abnormal expansion of CAG trinucleotide repeats. Neuroinflammation is a typical feature of most neurodegenerative diseases that leads to an array of pathological changes within the affected areas in the brain. The neurodegeneration in HD is also caused by aberrant immune response in the presence of aggregated mutant huntingtin protein. The effects of immune activation in HD nervous system are a relatively unexplored area of research. This paper summarises immunological features associated with development and progression of HD.

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