Huntington's Disease Research Articles

HAP40 modulates mutant Huntingtin aggregation and toxicity in Huntington’s disease mice

Huntington’s disease (HD) is a monogenic neurodegenerative disease, caused by the CAG trinucleotide repeat expansion in exon 1 of the Huntingtin (HTT) gene. The HTT gene encodes a large protein known to interact with many proteins. Huntingtin-associated protein 40 (HAP40) is one that shows high binding affinity with HTT and functions to maintain HTT conformation in vitro. However, the potential role of HAP40 in HD pathogenesis remains unknown. In this study, we found that the expression level of HAP40 is in parallel with HTT but inversely correlates with mutant HTT aggregates in mouse brains. Depletion of endogenous HAP40 in the striatum of HD140Q knock-in (KI) mice leads to enhanced mutant HTT aggregation and neuronal loss. Consistently, overexpression of HAP40 in the striatum of HD140Q KI mice reduced mutant HTT aggregation and ameliorated the behavioral deficits. Mechanistically, HAP40 preferentially binds to mutant HTT and promotes Lysine 48-linked ubiquitination of mutant HTT. Our results revealed that HAP40 is an important regulator of HTT protein homeostasis in vivo and hinted at HAP40 as a therapeutic target in HD treatment.

Polyglutamine-mediated ribotoxicity disrupts proteostasis and stress responses in Huntington's disease.

Huntington's disease (HD) is a neurodegenerative disorder caused by expansion of a CAG trinucleotide repeat in the Huntingtin (HTT) gene, encoding a homopolymeric polyglutamine (polyQ) tract. Although mutant HTT (mHTT) protein is known to aggregate, the links between aggregation and neurotoxicity remain unclear. Here we show that both translation and aggregation of wild-type HTT and mHTT are regulated by a stress-responsive upstream open reading frame and that polyQ expansions cause abortive translation termination and release of truncated, aggregation-prone mHTT fragments. Notably, we find that mHTT depletes translation elongation factor eIF5A in brains of symptomatic HD mice and cultured HD cells, leading to pervasive ribosome pausing and collisions. Loss of eIF5A disrupts homeostatic controls and impairs recovery from acute stress. Importantly, drugs that inhibit translation initiation reduce premature termination and mitigate this escalating cascade of ribotoxic stress and dysfunction in HD.

Predictive genetic testing for Huntington's disease: Exploring participant experiences of uncertainty and ambivalence between clinic appointments.

Ambivalence and uncertainty are key themes throughout the psychology of healthcare literature. This is especially so for individuals at risk of Huntington's disease (HD) deliberating the decision to undergo genetic testing because there is currently no treatment that modifies disease progression. A better understanding of the experience of making a decision about genetic prediction will help practitioners support and guide individuals through this process. Our aim was to capture participants' experiences of uncertainty and ambivalence in between their genetic counseling appointments. We explored these issues through the experiences of nine participants who were referred for predictive HD testing at four regional genetics services in England and Wales. Data consisted of recordings of clinic consultations, diaries, and an in-depth interview conducted at the end of the testing process. Data were analyzed thematically. Four themes were identified representing four possible futures, each future dependent on the decision to undergo testing and the result of that test. Our results showed that participants, as well as attending more to a future that represents their current situation of not having undergone predictive testing, also attended more to a distant future where a positive predictive result is received and symptoms have started. Participants attended less to the two futures that were more immediate once testing was undertaken (a future where a positive result is received and symptoms have not started and a future where a negative result is received). The use of diaries gave us a unique insight into these participants' experiences of ambivalence and uncertainty, psychological distress, and the emotional burden experienced. These findings help inform discussions within the clinic appointment as well as encourage researchers to consider diary use as a method of exploring what happens for individuals outside of clinical encounters.

Targeting TrkB-PSD-95 coupling to mitigate neurological disorders

Abstract Tropomyosin kinase receptor B (TrkB) signaling plays a pivotal role in dendritic growth and dendritic spine formation to promote learning and memory. The activity-dependent release of brain-derived neurotrophic factor at synapses binds to pre- or postsynaptic TrkB resulting in the strengthening of synapses, reflected by long-term potentiation. Postsynaptically, the association of postsynaptic density protein-95 with TrkB enhances phospholipase Cγ-Ca2+/calmodulin-dependent protein kinase II and phosphatidylinositol 3-kinase-mechanistic target of rapamycin signaling required for long-term potentiation. In this review, we discuss tyrosine kinase B receptor-postsynaptic density protein-95 coupling as a promising strategy to magnify brain-derived neurotrophic factor signaling towards the development of novel therapeutics for specific neurological disorders. A reduction of TrkB signaling has been observed in neurodegenerative disorders, such as Alzheimer's disease and Huntington's disease, and enhancement of postsynaptic density protein-95 association with TrkB signaling could mitigate the observed deficiency of neuronal connectivity in schizophrenia and depression. Treatment with brain-derived neurotrophic factor is problematic, due to poor pharmacokinetics, low brain penetration, and side effects resulting from activation of the p75 neurotrophin receptor or the truncated tyrosine kinase B receptor.T1 isoform. Although TrkB agonists and antibodies that activate TrkB are being intensively investigated, they cannot distinguish the multiple human TrkB splicing isoforms or cell type-specific functions. Targeting tyrosine kinase B receptor-postsynaptic density protein-95 coupling provides an alternative approach to specifically boost TrkB signaling at localized synaptic sites versus global stimulation that risks many adverse side effects.

Effects and mechanisms of computerized cognitive training in Huntington's disease: protocol for a pilot study

Huntington's disease (HD) causes progressive cognitive decline, with no available treatments. Computerized cognitive training (CCT) has shown efficacy in other populations, but its effects in HD are largely unknown. This pilot study will explore the effects and neural mechanisms of CCT in HD. The intervention group participants will complete 12 weeks of multidomain CCT. Control group participants will receive lifestyle education and access to CCT after the study. The primary outcome is change in processing speed. Secondary outcomes include – change in other cognitive domains, functional brain network connectivity (derived from MRI) and psychosocial function. Feasibility outcomes include rates of recruitment, adherence and retention. This study may provide insights into the effects of CCT in HD and guide future trials. Clinical Trial Registration: ACTRN12622000908730 ( ClinicalTrials.gov )

Blocking SLC7A11 attenuates the proliferation of esophageal squamous cell carcinoma cells

ABSTRACT The role of ferroptosis-associated gene SLC7A11 in esophageal cancer progression is largely unknown, therefore, the effects of blocking SLC7A11 on esophageal squamous cell carcinoma (ESCC) cells are evaluated. Results showed that SLC7A11 was overexpressed in ESCC tissues both in mRNA and protein levels. Blocking SLC7A11 using Erastin suppressed the proliferation and colony formation of ESCC cells, decreased cellular ATP levels, and improved ROS production. Sixty-three SLC7A11-binding proteins were identified using the IP-MS method, and these proteins were enriched in four signaling pathways, including spliceosome, ribosome, huntington disease, and diabetic cardiomyopathy. The deubiquitinase inhibitors PR-619, GRL0617, and P 22077 could reduce at least 40% protein expression level of SLC7A11 in ESCC cells, and PR-619 and GRL0617 exhibited suppressive effects on the cell viability and colony formation ability of KYSE30 cells, respectively. Erastin downregulated GPX4 and DHODH and also reduced the levels of β-catenin, p-STAT3, and IL-6 in ESCC cells. In conclusion, SLC7A11 was overexpressed in ESCC, and blocking SLC7A11 using Erastin mitigated malignant phenotypes of ESCC cells and downregulated key ferroptosis-associated molecules GPX4 and DHODH. The therapeutic potential of targeting SLC7A11 should be further evaluated in the future.

Advancements in CRISPR-Based Therapies for Genetic Modulation in Neurodegenerative Disorders.

: Neurodegenerative disorders pose significant challenges in the realm of healthcare, as these conditions manifest in complex, multifaceted ways, often attributed to genetic anomalies. With the emergence of CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) technology, a new frontier has been unveiled in the quest for targeted, precise genetic manipulation. This abstract explores the recent advancements and potential applications of CRISPR-based therapies in addressing genetic components contributing to various neurodegenerative disorders. The review delves into the foundational principles of CRISPR technology, highlighting its unparalleled ability to edit genetic sequences with unprecedented precision. In addition, it talks about the latest progress in using CRISPR to target specific genetic mutations linked to neurodegenerative diseases like Huntington's disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), and Parkinson's disease. It talks about the most important studies and trials that show how well and safely CRISPR-based therapies work. This shows how this technology can change genetic variants that cause diseases. Notably, the discussion emphasizes the challenges and ethical considerations associated with the implementation of CRISPR in clinical settings, including off-target effects, delivery methods, and long-term implications. Furthermore, the article explores the prospects and potential hurdles in the widespread application of CRISPR technology for treating neurodegenerative disorders. It touches upon the need for continued research, improved delivery mechanisms, and ethical frameworks to ensure responsible and equitable access to these groundbreaking therapies.

A programmable dual-targeting siRNA scaffold supports potent two-gene modulation in the central nervous system.

Divalent short-interfering RNA (siRNA) holds promise as a therapeutic approach allowing for the sequence-specific modulation of a target gene within the central nervous system (CNS). However, an siRNA modality capable of simultaneously modulating gene pairs would be invaluable for treating complex neurodegenerative disorders, where more than one pathway contributes to pathogenesis. Currently, the parameters and scaffold considerations for multi-targeting nucleic acid modalities in the CNS are undefined. Here, we propose a framework for designing unimolecular 'dual-targeting' divalent siRNAs capable of co-silencing two genes in the CNS. We systematically adjusted the original CNS-active divalent siRNA and identified that connecting two sense strands 3' and 5' through an intra-strand linker enabled a functional dual-targeting scaffold, greatly simplifying the synthetic process. Our findings demonstrate that the dual-targeting siRNA supports at least two months of maximal distribution and target silencing in the mouse CNS. The dual-targeting divalent siRNA is highly programmable, enabling simultaneous modulation of two different disease-relevant gene pairs (e.g. Huntington's disease: MSH3 and HTT; Alzheimer's disease: APOE and JAK1) with similar potency to a mixture of single-targeting divalent siRNAs against each gene. This work enhances the potential for CNS modulation of disease-related gene pairs using a unimolecular siRNA.

Gut Microbiota as a Modifier of Huntington's Disease Pathogenesis.

Huntingtin (HTT) protein is expressed in most cell lineages, and the toxicity of mutant HTT in multiple organs may contribute to the neurological and psychiatric symptoms observed in Huntington's disease (HD). The proteostasis and neurotoxicity of mutant HTT are influenced by the intracellular milieu and responses to environmental signals. Recent research has highlighted a prominent role of gut microbiota in brain and immune system development, aging, and the progression of neurological disorders. Several studies suggest that mutant HTT might disrupt the homeostasis of gut microbiota (known as dysbiosis) and impact the pathogenesis of HD. Dysbiosis has been observed in HD patients, and in animal models of the disease it coincides with mutant HTT aggregation, abnormal behaviors, and reduced lifespan. This review article aims to highlight the potential toxicity of mutant HTT in organs and pathways within the microbiota-gut-immune-central nervous system (CNS) axis. Understanding the functions of Wild-Type (WT) HTT and the toxicity of mutant HTT in these organs and the associated networks may elucidate novel pathogenic pathways, identify biomarkers and peripheral therapeutic targets for HD.

Atypical Presentations of Huntington Disease-like 2 in South African Individuals.

Huntington disease-like 2 (HDL2) is a neurodegenerative disorder, affecting only individuals of African ancestry. Full penetrance occurs in individuals with 40 repeats or more. To describe the phenotypic variability of HDL2 in a group of mixed ancestry individuals from South Africa. Eight patients were assessed with analysis of repeat size and magnetic resonance brain imaging. We applied the Unified Huntington's Disease Rating Scale (UHDRS), but in deceased patients (4), this was estimated from video material. Cognitive domains were more severely affected than motor; UHDRS motor scores were notable for bradykinesia, and to a slightly lesser extent, for rigidity and dystonia; a single patient had marked chorea. Repeat lengths ranged from 45 to 63 (median, 52). This South African group of mixed ancestry HDL2 individuals presented with severe cognitive and behavioral impairments, with lesser degrees or absence of chorea. This presentation is possibly related to large repeat sizes.

Molecular genetic analysis of cytosine-adenine-guanine repeats in huntingtin gene

Background: Huntington’s disease (HD) is a dominantly transmitted progressive neurodegenerative disorder due to abnormal expansion of cytosine-adenine-guanine (CAG) repeats in the huntingtin gene. Materials and Methods: The study involved a total of 35 HD patients identified through clinical evaluations. CAG repeats expansion analysis was conducted using polymerase chain reaction (PCR) to confirm positive cases. Results: Employing CAG flacking PCR in 35 cases, 19 tested positive, predominantly displaying CAG repeats in the range of 40–50. Noteworthy cases include a 5-month-old patient with 44 CAG repeats and an 80-year-old patient with 46 CAG repeats. Conclusion: The identification of the genetic defect in HD permits direct genetic testing to comprehend the complexities of HD in India, aiming for effective approaches in diagnosis, treatment, and prevention.

Transcriptomic Profiles Associated with Experimental Placebo Effects in Chronic Pain.

Gene expression networks associated with placebo effects are understudied; in this study, we identified transcriptomic profiles associated with placebo responsivity. Participants suffering from chronic pain underwent a verbal suggestion and conditioning paradigm with individually tailored thermal painful stimulations to elicit conditioned placebo effects. Participants reported pain intensity on a visual analog scale (VAS) anchored from zero = no pain to 100 = maximum imaginable pain. RNA was extracted from venous blood and RNA sequencing and validation tests were performed to identify differentially expressed genes (DEGs) associated with placebo effects, controlling for sex and level of pain. Unbiased enrichment analyses were performed to identify biological processes associated with placebo effects. Of the 10,700 protein-coding genes that passed quality control filters, 667 were found to be associated with placebo effects (FDR <0.05). Most genes (97%) upregulated were associated with larger placebo effects. The 17 top transcriptome-wide significant genes were further validated via RT-qPCR in an independent cohort of chronic pain participants. Six of them (CCDC85B, FBXL15, HAGH, PI3, SELENOM, and TNFRSF4) showed positive and significant (P < 0.05) correlation with placebo effects in the cohort. The overall DEGs were highly enriched in regulation of expression of SLITs and ROBOs (R-HSA-9010553, FDR = 1.26e-33), metabolism of RNA (R-HSA-8953854, FDR = 1.34e-30), Huntington's disease (hsa05016, FDR = 9.84e-31), and ribosome biogenesis (GO:0042254, FDR = 2.67e-15); alternations in these pathways might jeopardize the proneness to elicit placebo effects. Future studies are needed to replicate this finding and better understand the unique molecular dynamics of people who are more or less affected by pain and placebo.

A Journey through Huntington's Disease: Exploring Genetics, Neurobiology, and Therapeutic Advances

Huntington disease (HD) is a progressive neurodegenerative disease that is debilitating for families worldwide. Inherited in an autosomal dominant manner, HD results from a CAG expansion in the gene encoding the huntingtin protein. This mutation leads to a host of motor, cognitive, and psychiatric symptoms that generally appear in middle age. While spiny projection neurons in the striatum are the most vulnerable cell type in HD, notable atrophy occurs throughout the brain, including the white matter; for this reason, HD is now considered to be a brain-wide disease. The clinical features, ethics, and neurobiology of HD are discussed in this chapter. The chapter also reviews the exciting approaches being employed today to advance understanding of underlying mechanisms in an effort to develop therapies that would delay the onset and slow progression of this disease.

Let's get fat: emergence of S-acylation as a therapeutic target in Huntington disease.

Protein mislocalization is a key initial step in neurodegeneration, regardless of etiology, and has been linked to changes in the dynamic addition of saturated fatty acids to proteins, a process known as S-acylation. With the advent of new techniques to study S-acylation and the recent discovery of new enzymes that facilitate protein deacylation, novel small molecules are emerging as potential new therapeutic treatments. Huntington disease (HD) is a devastating, fatal neurodegenerative disease characterized by motor, cognitive, and psychiatric deficits caused by a CAG repeat expansion in the HTT gene. The protein that is mutated in HD, huntingtin, is less S-acylated which is associated with mutant HTT aggregation and cytotoxicity. Recent exciting findings indicate that restoring S-acylation in HD models using small molecule inhibitors of the deacylation enzymes is protective. Herein, we set out to describe the known roles of S-acylation in HD and how it can be targeted for therapeutic design.

PET Ligands for Imaging Mutant Huntingtin Aggregates: A Case Study in Non-For-Profit Scientific Management.

Positron emission tomography imaging of misfolded proteins with high-affinity and selective radioligands has played a vital role in expanding our knowledge of neurodegenerative diseases such as Parkinson's and Alzheimer's disease. The pathogenesis of Huntington's disease, a CAG trinucleotide repeat disorder, is similarly linked to the presence of protein fibrils formed from mutant huntingtin (mHTT) protein. Development of mHTT fibril-specific radioligands has been limited by the lack of structural knowledge around mHTT and a dearth of available hit compounds for medicinal chemistry refinement. Over the past decade, the Cure Huntington's Disease Initiative (CHDI), a non-for-profit scientific management organisation has orchestrated a large-scale screen of small molecules to identify high affinity ligands of mHTT, with lead compounds now reaching clinical maturity. Here we describe the mHTT radioligands developed to date and opportunities for further improvement of this radiotracer class.

Huntington Disease – Update on Recent Advances and a Look Toward the Future

Huntington Disease – Update on Recent Advances and a Look Toward the Future

The phosphodiesterase inhibitor, ibudilast ameliorates Huntington's disease pathology by modulating neuroinflammation and signaling pathway in a rat model

The phosphodiesterase inhibitor, ibudilast ameliorates Huntington's disease pathology by modulating neuroinflammation and signaling pathway in a rat model

Paradigms and Success Stories of Natural Products in Drug Discovery Against Neurodegenerative Disorders (NDDs).

Neurodegenerative disorders (NDDs) are multifaceted complex disorders that have put a great health and economic burden around the globe nowadays. The multi-factorial nature of NDDs has presented a great challenge in drug discovery and continuous efforts are in progress in search of suitable therapeutic candidates. Nature has a great wealth of active principles in its lap that has cured the human population since ancient times. Natural products have revealed several benefits over conventional synthetic medications and scientists have shifted their vision towards exploring the therapeutic potentials of natural products in the past few years. The structural mimicking of natural compounds to endogenous ligands has presented them as a potential therapeutic candidate to prevent the development of NDDs. In the presented review, authors have summarized demographical facts about various NDDs including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD) and various types of sclerosis in the brain. The significant findings of new active principles of natural origin along with their therapeutic potentials on NDDs have been included. Also, a description of clinical trials and patents on natural products has been enlisted in this compilation. Although natural products have shown promising success in drug discovery against NDDs, still their use is associated with several ethical issues which need to be solved in the upcoming time.

I123-FP-CIT (DaTSCAN) SPECT beyond the Most Common Causes of Parkinsonism: A Systematic Review.

As the diagnosis of Parkinson's disease (PD) is fundamentally clinical, the usefulness of ioflupane (123I) single-photon emission computed tomography (SPECT) or DaTSCAN as a diagnostic tool has been a matter of debate for years. The performance of DaTSCAN is generally recommended in the follow-up of patients with a clinically uncertain diagnosis, especially in those with a suspected essential tremor, drug-induced parkinsonism, or vascular parkinsonism. However, there is a dearth of DaTSCAN findings regarding neurodegenerative parkinsonisms besides PD and atypical parkinsonisms. To date, a specific nigrostriatal dopamine uptake pattern that would help differentiate PD from the most frequent atypical parkinsonisms is yet to be described. This fact is further complicated by the possible visualization of abnormalities in the uptake pattern in patients with rarer neurodegenerative parkinsonisms. We aimed to summarize the current literature regarding DaTSCAN findings in patients with rare neurodegenerative parkinsonisms. The PubMed database was systematically screened for studies in English or Spanish up to October 15, 2023, using search terms "DaTSCAN", "ioflupane", "DaT-SPECT", "123I-FP-CIT SPECT", "dopamine transporter imaging", and "[123I] FP-CIT SPECT". Duplicated publications and studies regarding PD, atypical parkinsonisms, dystonia-parkinsonism, essential tremor, and parkinsonism due to non-degenerative causes were excluded. The obtained results were reviewed and summarized, including DaTSCAN findings in fragile X-associated tremor/ataxia syndrome, prion diseases, Huntington's disease, spinocerebellar ataxia, hereditary spastic paraparesis, metabolic disorders, and other diseases (anti-IgLON5 disease, ring chromosome 20 syndrome, chorea-acanthocytosis, and neuronal ceroid lipofuscinosis). This review highlights the need to determine in the future the utility and cost-effectiveness of DaTSCAN, both as a diagnostic and a prognostic tool, in patients with parkinsonian symptoms in rare neurodegenerative diseases.

The characteristic and prognostic role of blood inflammatory markers in patients with Huntington's disease from China

The characteristic and prognostic role of blood inflammatory markers in patients with Huntington's disease from China