Levels of Interleukin-6 in Saliva, but Not Plasma, Correlate with Clinical Metrics in Huntington’s Disease Patients and Healthy Control Subjects

Growing evidence suggests that inflammatory responses, in both the brain and peripheral tissues, contribute to disease pathology in Huntington’s disease (HD), an inherited, progressive neurodegenerative disorder typically affecting adults in their 30–40 s. Hence, studies of inflammation-related markers in peripheral fluids might be useful to better characterize disease features. In this study, we measured levels of C-reactive protein (CRP), Interleukin-6 (IL-6), interleukin 1 beta (IL-1B), and alpha-amylase (AA) in saliva and plasma from n = 125 subjects, including n = 37 manifest HD patients, n = 36 premanifest patients, and n = 52 healthy controls, using immunoassays. We found increases in salivary levels of IL-6, IL-1B and CRP across different disease groups and increased levels of IL-6 in the plasma of HD patients as compared to premanifest patients and controls. The levels of salivary IL-6 were significantly correlated with each of the other salivary markers, as well as with IL-6 levels measured in plasma. Further, salivary IL-6 and IL-1B levels were significantly positively correlated with Total Motor Score (TMS) and chorea scores and negatively correlated with Total Functional Capacity (TFC) in HD patients, whereby in healthy control subjects, IL-6 was significantly negatively correlated with Montreal Cognitive Assessment (MoCA) and the Symbol Digit Modalities test (SDM). Interestingly, the plasma levels of IL-6 did not show similar correlations to any clinical measures in either HD or control subjects. These findings suggest that salivary IL-6 is particularly relevant as a potential non-invasive biomarker for HD symptoms. The advent of an effective, dependable salivary biomarker would meet the urgent need for a less invasive means of identifying and monitoring HD disease progression.

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Insights into kinetics, release, and behavioral effects of brain-targeted hybrid nanoparticles for cholesterol delivery in Huntington’s disease

10.1101/2020.11.24.395525 ◽

2020 ◽

Author(s):

Giulia Birolini ◽

Marta Valenza ◽

Ilaria Ottonelli ◽

Alice Passoni ◽

Monica Favagrossa ◽

...

Keyword(s):

Huntington's Disease ◽

Huntington’S Disease ◽

Neurodegenerative Disorder ◽

Polymeric Nanoparticles ◽

Cholesterol Biosynthesis ◽

Hybrid Nanoparticles ◽

Neural Cells ◽

Peripheral Tissues ◽

Brain Cholesterol ◽

The Brain

AbstractSupplementing brain cholesterol is emerging as a potential treatment for Huntington’s disease (HD), a genetic neurodegenerative disorder characterized, among other abnormalities, by inefficient brain cholesterol biosynthesis. However, delivering cholesterol to the brain is challenging due to the bloodbrain barrier (BBB), which prevents it from reaching the striatum, especially, with therapeutically relevant doses.Here we describe the distribution, kinetics, release, and safety of novel hybrid polymeric nanoparticles made of PLGA and cholesterol which were modified with an heptapeptide (g7) for BBB transit (hybrid-g7-NPs-chol). We show that these NPs rapidly reach the brain and target neural cells. Moreover, deuterium-labeled cholesterol from hybrid-g7-NPs-chol is released in a controlled manner within the brain and accumulates over time, while being rapidly removed from peripheral tissues and plasma. We confirm that systemic and repeated injections of the new hybrid-g7-NPs-chol enhanced endogenous cholesterol biosynthesis, prevented cognitive decline, and ameliorated motor defects in HD animals, without any inflammatory reaction.In summary, this study provides insights about the benefits and safety of cholesterol delivery through advanced brain-permeable nanoparticles for HD treatment.

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What, When and How to Measure—Peripheral Biomarkers in Therapy of Huntington’s Disease

International Journal of Molecular Sciences ◽

10.3390/ijms22041561 ◽

2021 ◽

Vol 22 (4) ◽

pp. 1561

Author(s):

Lukasz Przybyl ◽

Magdalena Wozna-Wysocka ◽

Emilia Kozlowska ◽

Agnieszka Fiszer

Keyword(s):

Huntington's Disease ◽

Huntington’S Disease ◽

Neurodegenerative Disorder ◽

Motor Deficits ◽

Or Efficiency ◽

Peripheral Tissues ◽

Disease Symptoms ◽

The Central Nervous System ◽

Inflammatory Proteins ◽

Scientific Attention

Among the main challenges in further advancing therapeutic strategies for Huntington’s disease (HD) is the development of biomarkers which must be applied to assess the efficiency of the treatment. HD is a dreadful neurodegenerative disorder which has its source of pathogenesis in the central nervous system (CNS) but is reflected by symptoms in the periphery. Visible symptoms include motor deficits and slight changes in peripheral tissues, which can be used as hallmarks for prognosis of the course of HD, e.g., the onset of the disease symptoms. Knowing how the pathology develops in the context of whole organisms is crucial for the development of therapy which would be the most beneficial for patients, as well as for proposing appropriate biomarkers to monitor disease progression and/or efficiency of treatment. We focus here on molecular peripheral biomarkers which could be used as a measurable outcome of potential therapy. We present and discuss a list of wet biomarkers which have been proposed in recent years to measure pre- and postsymptomatic HD. Interestingly, investigation of peripheral biomarkers in HD can unravel new aspects of the disease pathogenesis. This especially refers to inflammatory proteins or specific immune cells which attract scientific attention in neurodegenerative disorders.

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

Journal of the International Neuropsychological Society ◽

10.1017/s1355617712000288 ◽

2012 ◽

Vol 18 (4) ◽

pp. 689-696 ◽

Cited By ~ 11

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)

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iNKT Cell Activation Exacerbates the Development of Huntington’s Disease in R6/2 Transgenic Mice

Mediators of Inflammation ◽

10.1155/2019/3540974 ◽

2019 ◽

Vol 2019 ◽

pp. 1-10 ◽

Cited By ~ 2

Author(s):

Hyun Jung Park ◽

Sung Won Lee ◽

Wooseok Im ◽

Manho Kim ◽

Luc Van Kaer ◽

...

Keyword(s):

Immune System ◽

Huntington's Disease ◽

Huntington’S Disease ◽

Cell Activation ◽

Inflammatory Responses ◽

Neurodegenerative Disorder ◽

Inkt Cells ◽

Regulatory T Lymphocytes ◽

The Brain ◽

Invariant Natural Killer

Huntington’s disease (HD) is an inherited neurodegenerative disorder which is caused by a mutation of the huntingtin (HTT) gene. Although the pathogenesis of HD has been associated with inflammatory responses, if and how the immune system contributes to the onset of HD is largely unknown. Invariant natural killer T (iNKT) cells are a group of innate-like regulatory T lymphocytes that can rapidly produce various cytokines such as IFNγ and IL4 upon stimulation with the glycolipid α-galactosylceramide (α-GalCer). By employing both R6/2 Tg mice (murine HD model) and Jα18 KO mice (deficient in iNKT cells), we investigated whether alterations of iNKT cells affect the development of HD in R6/2 Tg mice. We found that Jα18 KO R6/2 Tg mice showed disease progression comparable to R6/2 Tg mice, indicating that the absence of iNKT cells did not have any significant effects on HD development. However, repeated activation of iNKT cells with α-GalCer facilitated HD progression in R6/2 Tg mice, and this was associated with increased infiltration of iNKT cells in the brain. Taken together, our results demonstrate that repeated α-GalCer treatment of R6/2 Tg mice accelerates HD progression, suggesting that immune activation can affect the severity of HD pathogenesis.

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The Novel Alpha-2 Adrenoceptor Inhibitor Beditin Reduces Cytotoxicity and Huntingtin Aggregates in Cell Models of Huntington’s Disease

Pharmaceuticals ◽

10.3390/ph14030257 ◽

2021 ◽

Vol 14 (3) ◽

pp. 257

Author(s):

Elisabeth Singer ◽

Lilit Hunanyan ◽

Magda M. Melkonyan ◽

Jonasz J. Weber ◽

Lusine Danielyan ◽

...

Keyword(s):

Huntington's Disease ◽

Huntington’S Disease ◽

Neurodegenerative Disorder ◽

Cell Model ◽

Resonance Energy Transfer ◽

Neuronal Cell ◽

Resonance Energy ◽

Terminal Deoxynucleotidyl Transferase ◽

Tunel Staining ◽

Cell Models

Huntington’s disease (HD) is a monogenetic neurodegenerative disorder characterized by the accumulation of polyglutamine-expanded huntingtin (mHTT). There is currently no cure, and therefore disease-slowing remedies are sought to alleviate symptoms of the multifaceted disorder. Encouraging findings in Alzheimer’s and Parkinson’s disease on alpha-2 adrenoceptor (α2-AR) inhibition have shown neuroprotective and aggregation-reducing effects in cell and animal models. Here, we analyzed the effect of beditin, a novel α2- adrenoceptor (AR) antagonist, on cell viability and mHTT protein levels in cell models of HD using Western blot, time-resolved Foerster resonance energy transfer (TR-FRET), lactate dehydrogenase (LDH) and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) cytotoxicity assays. Beditin decreases cytotoxicity, as measured by TUNEL staining and LDH release, in a neuronal progenitor cell model (STHdh cells) of HD and decreases the aggregation propensity of HTT exon 1 fragments in an overexpression model using human embryonic kidney (HEK) 293T cells. α2-AR is a promising therapeutic target for further characterization in HD models. Our data allow us to suggest beditin as a valuable candidate for the pharmaceutical manipulation of α2-AR, as it is capable of modulating neuronal cell survival and the level of mHTT.

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RNA Sequencing of Human Peripheral Blood Cells Indicates Upregulation of Immune-Related Genes in Huntington's Disease

Frontiers in Neurology ◽

10.3389/fneur.2020.573560 ◽

2020 ◽

Vol 11 ◽

Author(s):

Miguel A. Andrade-Navarro ◽

Katja Mühlenberg ◽

Eike J. Spruth ◽

Nancy Mah ◽

Adrián González-López ◽

...

Keyword(s):

Gene Expression ◽

Huntington's Disease ◽

Huntington’S Disease ◽

Peripheral Blood ◽

Blood Cells ◽

Trinucleotide Repeat ◽

Neurodegenerative Disorder ◽

Gene Expression Signature ◽

Interferon Response ◽

Peripheral Blood Cells

Huntington's disease (HD) is an autosomal dominantly inherited neurodegenerative disorder caused by a trinucleotide repeat expansion in the Huntingtin gene. As disease-modifying therapies for HD are being developed, peripheral blood cells may be used to indicate disease progression and to monitor treatment response. In order to investigate whether gene expression changes can be found in the blood of individuals with HD that distinguish them from healthy controls, we performed transcriptome analysis by next-generation sequencing (RNA-seq). We detected a gene expression signature consistent with dysregulation of immune-related functions and inflammatory response in peripheral blood from HD cases vs. controls, including induction of the interferon response genes, IFITM3, IFI6 and IRF7. Our results suggest that it is possible to detect gene expression changes in blood samples from individuals with HD, which may reflect the immune pathology associated with the disease.

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Huntington's Disease: An Immune Perspective

Neurology Research International ◽

10.1155/2011/563784 ◽

2011 ◽

Vol 2011 ◽

pp. 1-7 ◽

Cited By ~ 12

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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Esculetin Provides Neuroprotection against Mutant Huntingtin-Induced Toxicity in Huntington’s Disease Models

Pharmaceuticals ◽

10.3390/ph14101044 ◽

2021 ◽

Vol 14 (10) ◽

pp. 1044

Author(s):

Letizia Pruccoli ◽

Carlo Breda ◽

Gabriella Teti ◽

Mirella Falconi ◽

Flaviano Giorgini ◽

...

Keyword(s):

Huntington's Disease ◽

Huntington’S Disease ◽

Neuronal Death ◽

Trinucleotide Repeat ◽

Neurodegenerative Disorder ◽

Positive Impact ◽

Neuroprotective Effects ◽

Drosophila Model ◽

Exon 1 ◽

Transgenic Drosophila

Huntington’s disease (HD) is a neurodegenerative disorder caused by an abnormal CAG trinucleotide repeat expansion within exon 1 of the huntingtin (HTT) gene. This mutation leads to the production of mutant HTT (mHTT) protein which triggers neuronal death through several mechanisms. Here, we investigated the neuroprotective effects of esculetin (ESC), a bioactive phenolic compound, in an inducible PC12 model and a transgenic Drosophila melanogaster model of HD, both of which express mHTT fragments. ESC partially inhibited the progression of mHTT aggregation and reduced neuronal death through its ability to counteract the oxidative stress and mitochondria impairment elicited by mHTT in the PC12 model. The ability of ESC to counteract neuronal death was also confirmed in the transgenic Drosophila model. Although ESC did not modify the lifespan of the transgenic Drosophila, it still seemed to have a positive impact on the HD phenotype of this model. Based on our findings, ESC may be further studied as a potential neuroprotective agent in a rodent transgenic model of HD.

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Non-Cell Autonomous and Epigenetic Mechanisms of Huntington’s Disease

International Journal of Molecular Sciences ◽

10.3390/ijms222212499 ◽

2021 ◽

Vol 22 (22) ◽

pp. 12499

Author(s):

Chaebin Kim ◽

Ali Yousefian-Jazi ◽

Seung-Hye Choi ◽

Inyoung Chang ◽

Junghee Lee ◽

...

Keyword(s):

Huntington's Disease ◽

Huntington’S Disease ◽

Trinucleotide Repeat ◽

Neurodegenerative Disorder ◽

Involuntary Movement ◽

Therapeutic Approaches ◽

Exon 1 ◽

Human Chromosome 4 ◽

The Brain

Huntington’s disease (HD) is a rare neurodegenerative disorder caused by an expansion of CAG trinucleotide repeat located in the exon 1 of Huntingtin (HTT) gene in human chromosome 4. The HTT protein is ubiquitously expressed in the brain. Specifically, mutant HTT (mHTT) protein-mediated toxicity leads to a dramatic degeneration of the striatum among many regions of the brain. HD symptoms exhibit a major involuntary movement followed by cognitive and psychiatric dysfunctions. In this review, we address the conventional role of wild type HTT (wtHTT) and how mHTT protein disrupts the function of medium spiny neurons (MSNs). We also discuss how mHTT modulates epigenetic modifications and transcriptional pathways in MSNs. In addition, we define how non-cell autonomous pathways lead to damage and death of MSNs under HD pathological conditions. Lastly, we overview therapeutic approaches for HD. Together, understanding of precise neuropathological mechanisms of HD may improve therapeutic approaches to treat the onset and progression of HD.

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Innovative Therapeutic Approaches for Huntington’s Disease: From Nucleic Acids to GPCR-Targeting Small Molecules

Frontiers in Cellular Neuroscience ◽

10.3389/fncel.2021.785703 ◽

2021 ◽

Vol 15 ◽

Author(s):

Hidetoshi Komatsu

Keyword(s):

Nucleic Acid ◽

Huntington's Disease ◽

Huntington’S Disease ◽

High Throughput Screening ◽

Neurodegenerative Disorder ◽

Direct Injection ◽

Cag Repeat ◽

Great Promise ◽

Nucleic Acid Delivery ◽

Small Interfering Rnas

Huntington’s disease (HD) is a fatal neurodegenerative disorder due to an extraordinarily expanded CAG repeat in the huntingtin gene that confers a gain-of-toxic function in the mutant protein. There is currently no effective cure that attenuates progression and severity of the disease. Since HD is an inherited monogenic disorder, lowering the mutant huntingtin (mHTT) represents a promising therapeutic strategy. Huntingtin lowering strategies mostly focus on nucleic acid approaches, such as small interfering RNAs (siRNAs) and antisense oligonucleotides (ASOs). While these approaches seem to be effective, the drug delivery to the brain poses a great challenge and requires direct injection into the central nervous system (CNS) that results in substantial burden for patients. This review discusses the topics on Huntingtin lowering strategies with clinical trials in patients already underway and introduce an innovative approach that has the potential to deter the disease progression through the inhibition of GPR52, a striatal-enriched class A orphan G protein-coupled receptor (GPCR) that represents a promising therapeutic target for psychiatric disorders. Chemically simple, potent, and selective GPR52 antagonists have been discovered through high-throughput screening and subsequent structure-activity relationship studies. These small molecule antagonists not only diminish both soluble and aggregated mHTT in the striatum, but also ameliorate HD-like defects in HD mice. This therapeutic approach offers great promise as a novel strategy for HD therapy, while nucleic acid delivery still faces considerable challenges.

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