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Risk factors for suicidality in Huntington disease: An analysis of the 2CARE clinical trial.

OBJECTIVE: Most suicidality literature in Huntington disease (HD) is based on natural history studies or retrospective reviews, but reports on risk factors from clinical trials are limited. METHODS: We analyzed 609 participants from 2CARE, a randomized, double-blind, placebo-controlled clinical trial with up to 5 years of follow-up, for risk factors related to suicidality. The primary outcome variable was the time from randomization until the first occurrence of either suicidal ideation or attempt. We also considered time from randomization until the first suicide attempt as a secondary outco

Fibroblast growth factor 9 activates anti-oxidative functions of Nrf2 through ERK signalling in striatal cell models of Huntington's disease.

Huntington's disease (HD) is a heritable neurodegenerative disorder, and has been characterized as an increase of oxidative stress in brain regions. In our previous results, we showed fibroblast growth factor 9 (FGF9) provides neuroprotective functions to suppress cell death in HD striatal cells dominantly through ERK signalling. However, whether the working mechanism of FGF9 is related to anti-oxidative stress in HD is still unknown. In this study, STHdhQ7/Q7 (Q7) and STHdhQ111/Q111 (Q111) striatal knock-in cell lines were used to examine the neuroprotective effects of FGF9 against oxidative

Expression of brain-derived neurotrophic factor in astrocytes - Beneficial effects of glatiramer acetate in the R6/2 and YAC128 mouse models of Huntington's disease.

Glatiramer acetate (GA) is a FDA-approved drug which is licensed for the treatment of relapsing-remitting multiple sclerosis and which may exert neuroprotective effects via brain-derived neurotrophic factor (BDNF). In this study, we investigate effects of GA on BDNF expression especially in astrocytes in vitro and in vivo in brains of R6/2 and YAC128 transgenic mouse models of Huntington's disease (HD) where a pathogenic role of astroglial cells has recently been shown. We show that GA increases the expression of functionally active BDNF in astrocyte culture and in astrocytes of GA treated HD

Preconditioning mesenchymal stem cells with the mood stabilizers lithium and valproic acid enhances therapeutic efficacy in a mouse model of Huntington's disease.

Huntington's disease (HD) is a fatal neurodegenerative disorder caused by CAG repeat expansions in the huntingtin gene. Although, stem cell-based therapy has emerged as a potential treatment for neurodegenerative diseases, limitations remain, including optimizing delivery to the brain and donor cell loss after transplantation. One strategy to boost cell survival and efficacy is to precondition cells before transplantation. Because the neuroprotective actions of the mood stabilizers lithium and valproic acid (VPA) induce multiple pro-survival signaling pathways, we hypothesized that preconditio

The cytokine and endocannabinoid systems are co-regulated by NF-κB p65/RelA in cell culture and transgenic mouse models of Huntington's disease and in striatal tissue from Huntington's disease patients.

Transcriptional dysregulation is a major pathological feature of Huntington's disease (HD). The goal of this study was to understand how p65/RelA co-regulated genes, specifically those of the cytokine and endocannabinoid systems, were affected in HD. p65/RelA levels were lower in human HD tissue and R6/2 HD mice, as were the levels of the type 1 cannabinoid receptor (CB1), IL-1β, IL-8, CCL5, GM-CSF, MIP-1β, and TNFα, all of which may be regulated by p65/RelA. Activation of p65/RelA restored CB1 and CCL5 expression in STHdh cell models of HD. Therefore, p65/RelA activation may normalize the exp

CYP46A1 gene therapy deciphers the role of brain cholesterol metabolism in Huntington's disease.

Dysfunctions in brain cholesterol homeostasis have been extensively related to brain disorders. The main pathway for brain cholesterol elimination is its hydroxylation into 24S-hydroxycholesterol by the cholesterol 24-hydrolase, CYP46A1. Increasing evidence suggests that CYP46A1 has a role in the pathogenesis and progression of neurodegenerative disorders, and that increasing its levels in the brain is neuroprotective. However, the mechanisms underlying this neuroprotection remain to be fully understood. Huntington's disease is a fatal autosomal dominant neurodegenerative disease caused by an

Targeting H3K4 trimethylation in Huntington disease.

Transcriptional dysregulation is an early feature of Huntington disease (HD). We observed gene-specific changes in histone H3 lysine 4 trimethylation (H3K4me3) at transcriptionally repressed promoters in R6/2 mouse and human HD brain. Genome-wide analysis showed a chromatin signature for this mark. Reducing the levels of the H3K4 demethylase SMCX/Jarid1c in primary neurons reversed down-regulation of key neuronal genes caused by mutant Huntingtin expression. Finally, reduction of SMCX/Jarid1c in primary neurons from BACHD mice or the single Jarid1 in a Drosophila HD model was protective. There

The melatonin MT1 receptor axis modulates mutant Huntingtin-mediated toxicity.

Melatonin mediates neuroprotection in several experimental models of neurodegeneration. It is not yet known, however, whether melatonin provides neuroprotection in genetic models of Huntington's disease (HD). We report that melatonin delays disease onset and mortality in a transgenic mouse model of HD. Moreover, mutant huntingtin (htt)-mediated toxicity in cells, mice, and humans is associated with loss of the type 1 melatonin receptor (MT1). We observe high levels of MT1 receptor in mitochondria from the brains of wild-type mice but much less in brains from HD mice. Moreover, we demonstrate t

Adverse effects of dopamine potentiation by long-term treatment with selegiline.

A patient with triosephosphate isomerase (TPI) deficiency exhibited worsening of abnormal involuntary movements of the dystonic type and developed psychiatric symptoms while on selegiline. When selegiline was stopped after 9 years of treatment, abnormal involuntary movements improved to pretreatment level and psychiatric behaviour returned to normal. Monoamine oxidase-B platelet activity was low in this patient.

Expression, pharmacology and functional activity of adenosine A1 receptors in genetic models of Huntington's disease.

Adenosine A1 receptor (A1R) stimulation exerts beneficial effects in response to various insults to the brain and, although it was found neuroprotective in a lesional model of Huntington's disease (HD), the features of this receptor in genetic models of HD have never been explored. In the present study we characterized the expression, affinity and functional effects of A1Rs in R6/2 mice (the most widely used transgenic model of HD) and in a cellular model of HD. Binding studies revealed that the density of A1Rs was significantly reduced in the cortex and the striatum of R6/2 mice compared to a

Activation of NPY-Y2 receptors ameliorates disease pathology in the R6/2 mouse and PC12 cell models of Huntington's disease.

Huntington's disease (HD) is a monogenic inherited polyglutamine-mediated neurodegenerative disorder for which effective therapies are currently unavailable. Neuropeptide Y (NPY) has been implicated as a potential therapeutic target in several neurodegenerative diseases, including HD. However, its mechanisms of action in the context of HD pathology remain unknown. Here, we investigated the beneficial effects of Y2 receptor (Y2R) activation with NPY or Y2R selective agonist NPY13-36 in the R6/2 mouse and PC12 cell models of HD. Also, we explored the effects of selective pharmacological blockage

Behavioral and in vivo electrophysiological evidence for presymptomatic alteration of prefrontostriatal processing in the transgenic rat model for huntington disease.

Cognitive decline precedes motor symptoms in Huntington disease (HD). A transgenic rat model for HD carrying only 51 CAG repeats recapitulates the late-onset HD phenotype. Here, we assessed prefrontostriatal function in this model through both behavioral and electrophysiological assays. Behavioral examination consisted in a temporal bisection task within a supra-second range (2 vs.8 s), which is thought to involve prefrontostriatal networks. In two independent experiments, the behavioral analysis revealed poorer temporal sensitivity as early as 4 months of age, well before detection of overt m

The novel KMO inhibitor CHDI-340246 leads to a restoration of electrophysiological alterations in mouse models of Huntington's disease.

Dysregulation of the kynurenine (Kyn) pathway has been associated with the progression of Huntington's disease (HD). In particular, elevated levels of the kynurenine metabolites 3-hydroxy kynurenine (3-OH-Kyn) and quinolinic acid (Quin), have been reported in the brains of HD patients as well as in rodent models of HD. The production of these metabolites is controlled by the activity of kynurenine mono-oxygenase (KMO), an enzyme which catalyzes the synthesis of 3-OH-Kyn from Kyn. In order to determine the role of KMO in the phenotype of mouse models of HD, we have developed a potent and select

Implantation of undifferentiated and pre-differentiated human neural stem cells in the R6/2 transgenic mouse model of Huntington's disease.

BACKGROUND: Cell therapy is a potential therapeutic approach for several neurodegenetative disease, including Huntington Disease (HD). To evaluate the putative efficacy of cell therapy in HD, most studies have used excitotoxic animal models with only a few studies having been conducted in genetic animal models. Genetically modified animals should provide a more accurate representation of human HD, as they emulate the genetic basis of its etiology. RESULTS: In this study, we aimed to assess the therapeutic potential of a human striatal neural stem cell line (STROC05) implanted in the R6/2 tran

Modulation of lipid peroxidation and mitochondrial function improves neuropathology in Huntington's disease mice.

Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder. Oxidative damage has been associated with pathological neuronal loss in HD. The therapeutic modulation of oxidative stress and mitochondrial function using low molecular weight compounds may be an important strategy for delaying the onset and slowing the progression of HD. In the present study, we found a marked increase of 4-hydroxy-2-nonenal (4-HNE) adducts, a lipid peroxidation marker, in the caudate and putamen of HD brains and in the striatum of HD mice. Notably, 4-HNE immunoreactivity was colocalized with muta

Safety, tolerability, and efficacy of PBT2 in Huntington's disease: a phase 2, randomised, double-blind, placebo-controlled trial.

BACKGROUND: PBT2 is a metal protein-attenuating compound that might reduce metal-induced aggregation of mutant huntingtin and has prolonged survival in a mouse model of Huntington's disease. We aimed to assess the safety, tolerability, and efficacy of PBT2 in patients with Huntington's disease. METHODS: In this 26-week, randomised, double-blind, placebo-controlled trial, adults (≥25 years old) with early-stage to mid-stage Huntington's disease were randomly assigned (1:1:1) by a centralised interactive response system to once daily PBT2 250 mg, PBT2 100 mg, or placebo. Randomisation was strat

DNA methylation study of Huntington's disease and motor progression in patients and in animal models.

Although Huntington's disease (HD) is a well studied Mendelian genetic disorder, less is known about its associated epigenetic changes. Here, we characterize DNA methylation levels in six different tissues from 3 species: a mouse huntingtin (Htt) gene knock-in model, a transgenic HTT sheep model, and humans. Our epigenome-wide association study (EWAS) of human blood reveals that HD mutation status is significantly (p < 10-7) associated with 33 CpG sites, including the HTT gene (p = 6.5 × 10-26). These Htt/HTT associations were replicated in the Q175 Htt knock-in mouse model (p = 6.0 × 10-8) an

Unraveling Molecular and Genetic Insights into Neurodegenerative Diseases: Advances in Understanding Alzheimer's, Parkinson's, and Huntington's Diseases and Amyotrophic Lateral Sclerosis.

Neurodegenerative diseases are, according to recent studies, one of the main causes of disability and death worldwide. Interest in molecular genetics has started to experience exponential growth thanks to numerous advancements in technology, shifts in the understanding of the disease as a phenomenon, and the change in the perspective regarding gene editing and the advantages of this action. The aim of this paper is to analyze the newest approaches in genetics and molecular sciences regarding four of the most important neurodegenerative disorders: Alzheimer's disease, Parkinson's disease, Hunti

Совпадение в полном тексте источника
… Figure 2 The huntingtin protein can take on various forms and undergo changes depending on the expression of the HTT gene. Normally, the expression of HTT results in the production of an RNA transcript that codes for the complete huntingtin protein. … On the other hand, the full-length huntingtin protein includes the HTT exon1 sequence, as well as ordered and disordered protein segments represented by boxes and loops, respectively. …

GLP-1 Рецептор агонисты в неврологических расстройствах: от механизмов к клиническому переводу.

Глукагон-подобный peptide-1 агонисты рецепторов или GLP-1RAs, были использованы годами для обработки типа 2 диабет и ожирение. Совсем недавно стало ясно, что эти рецепторы широко распространяются по всей центральной нервной системе (СНС), что расширило возможность повторного использования этих лекарств для лечения неврологических расстройств. В этом обзоре мы анализируем улики по целому ряду неврологических условий, обсуждаем основные механизмы, которые, как предполагается, объясняют их нейрозащитные эффекты, и указываем на препятствия, которые еще предстоит устранить, прежде чем их можно буде

IL-34 в неврологическом гомеостазисе и его многогранная роль в заболеваниях центральной нервной системы.

Interleukin-34 (IL-34), лиганд для рецептора макрофажных колоний (CSF1R), играет незаменимую роль в развитии и поддержании гомеостазиса центральной нервной системы (CNS). В настоящем обзоре систематически излагаются основные механизмы, с помощью которых ось сигнала IL-34/CSF1R регулирует развитие, колонизацию и функциональную дифференциацию иммунных клеток-резидентов, включая микроглию и макрофаги, связанные с границами (BAM). Она подчеркивает свою роль в критических физиологических процессах, таких, как синаптическое обрезка, созревание нервной цепи и поддержание целостности мозгового барьера

Совпадение в полном тексте источника
… The mutation leads to the production of a toxic mutant huntingtin protein (mHTT) containing an expanded polyglutamine (polyQ) tract ( 95 ). mHTT is readily cleaved by proteases into mutant huntingtin exon 1 fragments (mHTTx1) with amyloid-like properties. … Notably, in a transgenic mouse model of Huntington’s disease (HD), luteolin treatment significantly extended lifespan by 25.5%, improved motor coordination and balance, reduced serum neurofilament light chain (NfL) levels (a marker of neuronal damage), and decreased mutant huntingtin protein aggregation …