New Perspectives on Emotional Processing in People with Symptomatic Huntington’s Disease: Impaired Emotion Regulation and Recognition of Emotional Body Language†

Abstract Objective Emotion regulation and emotional body language (EBL) recognition represent two fundamental components of emotional processing that have recently seen a considerable surge in research interest, in part due to the role they play in optimizing mental health. This appears to be particularly true for clinical conditions that can profoundly affect emotional functioning. Among these is Huntington’s disease (HD), a neurodegenerative disorder that is associated with several psychological difficulties and cognitive impairments, including well-established deficits in facial emotion recognition. However, although the theoretical case for impairments is strong, the current evidence in HD on other components such as emotion regulation and EBL recognition is sparse. Method In this study, it was hypothesized that emotion regulation and recognition of EBL are impaired in people with symptomatic HD, and that these impairments significantly and positively correlate with each other. A between-subjects design was adopted to compare 13 people with symptomatic HD with 12 non-affected controls matched for age and education. Results The results showed that emotion regulation and EBL recognition were significantly impaired in individuals with HD. Moreover, a significant positive correlation was observed between facial and EBL recognition impairments, whereas EBL performance was negatively related to the disease stage. However, emotion regulation and recognition performances were not significantly correlated. Conclusions This investigation represents the first evidence of a deficit of emotion regulation and EBL recognition in individuals with HD. The clinical implications of these findings are explored, and indications for future research are proposed.

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Correlative light and electron microscopy suggests that mutant huntingtin dysregulates the endolysosomal pathway in presymptomatic Huntington’s disease

Acta Neuropathologica Communications ◽

10.1186/s40478-021-01172-z ◽

2021 ◽

Vol 9 (1) ◽

Author(s):

Ya Zhou ◽

Thomas R. Peskett ◽

Christian Landles ◽

John B. Warner ◽

Kirupa Sathasivam ◽

...

Keyword(s):

Electron Microscopy ◽

Huntington's Disease ◽

Huntington’S Disease ◽

Neurodegenerative Disorder ◽

Late Onset ◽

Light And Electron Microscopy ◽

Yeast Cells ◽

Disease Stage ◽

Dependent Manner ◽

Residual Bodies

AbstractHuntington’s disease (HD) is a late onset, inherited neurodegenerative disorder for which early pathogenic events remain poorly understood. Here we show that mutant exon 1 HTT proteins are recruited to a subset of cytoplasmic aggregates in the cell bodies of neurons in brain sections from presymptomatic HD, but not wild-type, mice. This occurred in a disease stage and polyglutamine-length dependent manner. We successfully adapted a high-resolution correlative light and electron microscopy methodology, originally developed for mammalian and yeast cells, to allow us to correlate light microscopy and electron microscopy images on the same brain section within an accuracy of 100 nm. Using this approach, we identified these recruitment sites as single membrane bound, vesicle-rich endolysosomal organelles, specifically as (1) multivesicular bodies (MVBs), or amphisomes and (2) autolysosomes or residual bodies. The organelles were often found in close-proximity to phagophore-like structures. Immunogold labeling localized mutant HTT to non-fibrillar, electron lucent structures within the lumen of these organelles. In presymptomatic HD, the recruitment organelles were predominantly MVBs/amphisomes, whereas in late-stage HD, there were more autolysosomes or residual bodies. Electron tomograms indicated the fusion of small vesicles with the vacuole within the lumen, suggesting that MVBs develop into residual bodies. We found that markers of MVB-related exocytosis were depleted in presymptomatic mice and throughout the disease course. This suggests that endolysosomal homeostasis has moved away from exocytosis toward lysosome fusion and degradation, in response to the need to clear the chronically aggregating mutant HTT protein, and that this occurs at an early stage in HD pathogenesis.

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Cortical Network Dynamics Is Altered in Mouse Models of Huntington’s Disease

Cerebral Cortex ◽

10.1093/cercor/bhz245 ◽

2019 ◽

Vol 30 (4) ◽

pp. 2372-2388 ◽

Cited By ~ 1

Author(s):

Elissa J Donzis ◽

Ana María Estrada-Sánchez ◽

Tim Indersmitten ◽

Katerina Oikonomou ◽

Conny H Tran ◽

...

Keyword(s):

Huntington's Disease ◽

Huntington’S Disease ◽

Cortical Neurons ◽

Laser Scanning ◽

Neurodegenerative Disorder ◽

Network Dynamics ◽

Laser Scanning Microscopy ◽

Disease Stage ◽

Motor Cortical ◽

Q175 Mice

Abstract Huntington’s disease (HD) is a neurodegenerative disorder characterized by involuntary movements, cognitive deficits, and psychiatric disturbances. Although evidence indicates that projections from motor cortical areas play a key role in the development of dysfunctional striatal activity and motor phenotype, little is known about the changes in cortical microcircuits and their role in the development of the HD phenotype. Here we used two-photon laser-scanning microscopy to evaluate network dynamics of motor cortical neurons in layers II/III in behaving transgenic R6/2 and knock-in Q175+/− mice. Symptomatic R6/2 mice displayed increased motion manifested by a significantly greater number of motion epochs, whereas symptomatic Q175 mice displayed decreased motion. In both models, calcium transients in symptomatic mice displayed reduced amplitude, suggesting decreased bursting activity. Changes in frequency were genotype- and time-dependent; for R6/2 mice, the frequency was reduced during both motion and nonmotion, whereas in symptomatic Q175 mice, the reduction only occurred during nonmotion. In presymptomatic Q175 mice, frequency was increased during both behavioral states. Interneuronal correlation coefficients were generally decreased in both models, suggesting disrupted interneuronal communication in HD cerebral cortex. These results indicate similar and contrasting effects of the HD mutation on cortical ensemble activity depending on mouse model and disease stage.

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Correlative light and electron microscopy reveals that mutant huntingtin dysregulates the endolysosomal pathway in presymptomatic Huntington’s disease

10.1101/2021.03.05.433899 ◽

2021 ◽

Author(s):

Ya Zhou ◽

Thomas R. Peskett ◽

Christian Landles ◽

John B. Warner ◽

Kirupa Sathasivam ◽

...

Keyword(s):

Electron Microscopy ◽

Huntington's Disease ◽

Huntington’S Disease ◽

Neurodegenerative Disorder ◽

Late Onset ◽

Light And Electron Microscopy ◽

Yeast Cells ◽

Disease Stage ◽

Dependent Manner ◽

Residual Bodies

AbstractHuntington’s disease (HD) is a late onset, inherited neurodegenerative disorder for which early pathogenic events remain poorly understood. Here we show that mutant exon 1 HTT proteins are recruited to a subset of cytoplasmic aggregates in the cell bodies of neurons in brain sections from presymptomatic HD, but not wild-type, mice. This occurred in a disease stage and polyglutamine-length dependent manner. We successfully adapted a high-resolution correlative light and electron microscopy methodology, originally developed for mammalian and yeast cells, to allow us to correlate light microscopy and electron microscopy images on the same brain section within an accuracy of 100 nm. Using this approach, we identified these recruitment sites as single membrane bound, vesicle-rich endolysosomal organelles, specifically as (i) multivesicular bodies (MVBs), or amphisomes and (ii) autolysosomes or residual bodies. The organelles were often found in close proximity to phagophore-like structures. Immunogold labeling localized mutant HTT to non-fibrillar, electron lucent structures within the lumen of these organelles. In presymptomatic HD, the recruitment organelles were predominantly MVBs/amphisomes, whereas in late-stage HD, there were more autolysosomes or residual bodies. Electron tomograms indicated the fusion of small vesicles with the vacuole within the lumen, suggesting that MVBs develop into residual bodies. We found that markers of MVB-related exocytosis were depleted in presymptomatic mice and throughout the disease course. This suggests that endolysosomal homeostasis has moved away from exocytosis toward lysosome fusion and degradation, in response to the need to clear the chronically aggregating mutant HTT protein, and that this occurs at an early stage in 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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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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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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