A novel pathogenic pathway of immune activation detectable before clinical onset in Huntington's disease

Huntington's disease (HD) is an inherited neurodegenerative disorder characterized by both neurological and systemic abnormalities. We examined the peripheral immune system and found widespread evidence of innate immune activation detectable in plasma throughout the course of HD. Interleukin 6 levels were increased in HD gene carriers with a mean of 16 years before the predicted onset of clinical symptoms. To our knowledge, this is the earliest plasma abnormality identified in HD. Monocytes from HD subjects expressed mutant huntingtin and were pathologically hyperactive in response to stimulation, suggesting that the mutant protein triggers a cell-autonomous immune activation. A similar pattern was seen in macrophages and microglia from HD mouse models, and the cerebrospinal fluid and striatum of HD patients exhibited abnormal immune activation, suggesting that immune dysfunction plays a role in brain pathology. Collectively, our data suggest parallel central nervous system and peripheral pathogenic pathways of immune activation in HD.

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

Journal of Huntington s Disease ◽

10.3233/jhd-200446 ◽

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.

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Early epigenomic and transcriptional changes reveal Elk-1 transcription factor as a therapeutic target in Huntington’s disease

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1908113116 ◽

2019 ◽

Vol 116 (49) ◽

pp. 24840-24851 ◽

Cited By ~ 4

Author(s):

Ferah Yildirim ◽

Christopher W. Ng ◽

Vincent Kappes ◽

Tobias Ehrenberger ◽

Siobhan K. Rigby ◽

...

Keyword(s):

Transcription Factor ◽

Huntington's Disease ◽

Huntington’S Disease ◽

Neurodegenerative Disorder ◽

Disease Onset ◽

Beneficial Effects ◽

Transcriptional Dysregulation ◽

Clinical Onset ◽

Transcriptional Changes ◽

Chromatin Profiling

Huntington’s disease (HD) is a chronic neurodegenerative disorder characterized by a late clinical onset despite ubiquitous expression of the mutant Huntingtin gene (HTT) from birth. Transcriptional dysregulation is a pivotal feature of HD. Yet, the genes that are altered in the prodromal period and their regulators, which present opportunities for therapeutic intervention, remain to be elucidated. Using transcriptional and chromatin profiling, we found aberrant transcription and changes in histone H3K27acetylation in the striatum of R6/1 mice during the presymptomatic disease stages. Integrating these data, we identified the Elk-1 transcription factor as a candidate regulator of prodromal changes in HD. Exogenous expression of Elk-1 exerted beneficial effects in a primary striatal cell culture model of HD, and adeno-associated virus-mediated Elk-1 overexpression alleviated transcriptional dysregulation in R6/1 mice. Collectively, our work demonstrates that aberrant gene expression precedes overt disease onset in HD, identifies the Elk-1 transcription factor as a key regulator linked to early epigenetic and transcriptional changes in HD, and presents evidence for Elk-1 as a target for alleviating molecular pathology in HD.

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HTT silencing delays onset and slows progression of Huntington’s disease like phenotype: Monitoring with a novel neurovascular biomarker

10.1101/2020.11.17.386631 ◽

2020 ◽

Author(s):

Hongshuai Liu ◽

Chuangchuang Zhang ◽

Jiadi Xu ◽

Jing Jin ◽

Liam Cheng ◽

...

Keyword(s):

Huntington's Disease ◽

Huntington’S Disease ◽

Clinical Symptoms ◽

Neurodegenerative Disorder ◽

Functional Neuroimaging ◽

Motor Deficits ◽

Striatal Neurons ◽

Gene Coding ◽

Allele Specific ◽

Noninvasive Biomarkers

AbstractHuntington’s disease (HD) is a dominantly inherited, fatal neurodegenerative disorder caused by a CAG expansion in the Huntingtin (HTT) gene, coding for pathologic mutant HTT protein (mHTT). Because of its gain-of-function mechanism and monogenic etiology, strategies to lower HTT are being actively investigated as disease-modifying therapies. Most approaches are currently targeted at the manifest HD stage, when clinical outcomes are used to evaluate the effectiveness of therapy. However, as almost 50% of striatal volume has been lost at the time of onset of manifest HD it would be preferable to begin therapy in the premanifest period. An unmet challenge is how to evaluate therapeutic efficacy before the presence of clinical symptoms as outcome measures. To address this, we have been developing more sensitive biomarkers such as functional neuroimaging with the goal of identifying noninvasive biomarkers that provide insight into the best time to introduce HTT-lowering treatment. In this study, we mapped the temporal trajectories of arteriolar cerebral blood volumes (CBVa) using inflow-based vascular-space-occupancy (iVASO) MRI technique in an HD mouse model. Significantly elevated CBVa was evident in premanifest zQ175 HD mice prior to motor deficits and striatal atrophy, recapitulating altered CBVa in human premanifest HD. CRISPR/Cas9-mediated non-allele-specific HTT silencing in striatal neurons restored altered CBVa in premanifest zQ175 mice, delayed onset of striatal atrophy, and slowed the progression of motor phenotype and brain pathology. This study showed the potential of CBVa as a noninvasive fMRI biomarker for premanifest HD clinical trials and demonstrates long-term benefits of introducing an HTT lowering treatment in the premanifest HD.

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Faculty Opinions recommendation of Identification of Genetic Factors that Modify Clinical Onset of Huntington's Disease.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.725690862.793517624 ◽

2016 ◽

Author(s):

Melanie Bahlo

Keyword(s):

Huntington's Disease ◽

Huntington’S Disease ◽

Genetic Factors ◽

Clinical Onset

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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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