YAC128 mouse

Huntington's disease is an inherited neurodegenerative disorder for which a wide range of disease-modifying therapies are in development and the availability of biomarkers to monitor treatment response is essential for the success of clinical trials. Baseline levels of neurofilament light chain in CSF and plasma have been shown to be effective in predicting clinical disease status, subsequent clinical progression and brain atrophy. The identification of further sensitive prognostic fluid biomarkers is an active research area, and total-Tau and YKL-40 levels have been shown to be increased in CSF from Huntington's disease mutation carriers...

In Huntington disease (HD), the mutant huntingtin (mtHTT) protein is the principal cause of pathological changes that initiate primarily along the cortico-striatal axis. mtHTT is ubiquitously expressed and there is, accordingly, growing recognition that HD is a systemic disorder with functional interplay between the brain and the periphery. We have developed a monoclonal antibody, C6-17, targeting an exposed region of HTT near the aa586 Caspase 6 cleavage site. As recently published, mAB C6-17 can block cell-to-cell propagation of mtHTT in vitro...

Environmental deprivation can have deleterious effects on adaptive myelination and oligodendroglia function. Early stage Huntington disease (HD) is characterised by white-matter myelin abnormalities in both humans and animal models. However, whether deprived environments exacerbate myelin-related pathological features of HD is not clearly understood. Here, we investigated the impact of deprivation and social isolation on ultrastructural features of myelin in the corpus callosum of the YAC128 mouse model of HD and wildtype (WT) mice using transmission electron microscopy...

In Huntington disease, cellular toxicity is particularly caused by toxic protein fragments generated from the mutant huntingtin (HTT) protein. By modifying the HTT protein, we aim to reduce proteolytic cleavage and ameliorate the consequences of mutant HTT without lowering total HTT levels. To that end, we use an antisense oligonucleotide (AON) that targets HTT pre-mRNA and induces partial skipping of exon 12, which contains the critical caspase-6 cleavage site. Here, we show that AON-treatment can partially restore the phenotype of YAC128 mice, a mouse model expressing the full-length human HTT gene including 128 CAG-repeats...

Cortical-striatal synaptic dysfunction, including enhanced toxic signaling by extrasynaptic N-methyl-d-aspartate receptors (eNMDARs), precedes neurodegeneration in Huntington disease (HD). A previous study showed Activin A, whose transcription is upregulated by calcium influx via synaptic NMDARs, suppresses eNMDAR signaling. Therefore, we examined the role of Activin A in the YAC128 HD mouse model, comparing it to wild-type controls. We found decreased Activin A secretion in YAC128 cortical-striatal co-cultures, while Activin A overexpression in this model rescued altered eNMDAR expression...

There are currently no drugs that meaningfully slow down the progression of Huntington's disease (HD). Moreover, drug candidates against a single molecular target have not had significant success. Therefore, a different approach to HD drug discovery is needed. Previously we showed that the flavonol fisetin is efficacious in mouse and fly models of HD (Hum. Mol. Gen. 20:261, 2011). It is also effective in animal models of Alzheimer's disease (AD), ischemic stroke, and the CNS complications of diabetes, all of which share some pathological features with HD...

Huntington's disease (HD) is a progressive and irreversible neurodegenerative disease leading to the inability to carry out daily activities and for which no cure exists. The underlying mechanisms of the disease have not been fully elucidated yet. Matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) allows the spatial information of proteins to be obtained upon the tissue sections without homogenisation. In this study, we aimed to examine proteomic alterations in the brain tissue of an HD mouse model with MALDI-MSI coupled to LC-MS/MS system...

Huntington disease (HD) is an adult-onset neurodegenerative disorder that is caused by a trinucleotide CAG repeat expansion in the HTT gene that codes for the protein huntingtin (HTT in humans or Htt in mice). HTT is a multi-functional, ubiquitously expressed protein that is essential for embryonic survival, normal neurodevelopment, and adult brain function. The ability of wild-type HTT to protect neurons against various forms of death raises the possibility that loss of normal HTT function may worsen disease progression in HD...

Action potential-independent (miniature) neurotransmission occurs at all chemical synapses, but remains poorly understood, particularly in pathological contexts. Axonal endoplasmic reticulum (ER) Ca2+ stores are thought to influence miniature neurotransmission, and aberrant ER Ca2+ handling is implicated in progression of Huntington disease (HD). Here, we report elevated miniature excitatory postsynaptic current (mEPSC) frequencies in recordings from YAC128 mouse (HD-model) neurons (from cortical cultures and striatum-containing brain slices - both from male and female animals)...

Huntington's disease (HD) is a neurodegenerative disorder, of which pathogenesis is caused by a polyglutamine expansion in the amino-terminus of huntingtin gene that resulted in the aggregation of mutant HTT proteins. HD is characterized by progressive motor dysfunction, cognitive impairment and neuropsychiatric disturbances. Histone deacetylase 6 (HDAC6), a microtubule-associated deacetylase, has been shown to induce transport- and release-defect phenotypes in HD models, whilst treatment with HDAC6 inhibitors ameliorates the phenotypic effects of HD by increasing the levels of α-tubulin acetylation, as well as decreasing the accumulation of mutant huntingtin (mHTT) aggregates, suggesting HDAC6 inhibitor as a HD therapeutics...

Huntington's disease (HD) is a neurodegenerative disease caused by a polyglutamine expansion in the huntingtin gene. Neurodegeneration first occurs in the striatum, accompanied by an elevation in inflammatory cytokines. Using the presymptomatic male YAC128 HD model mouse, we examined the synaptic input onto the striatal medium spiny neurons to look for early changes that precede degeneration. We observed an increase in excitatory synaptic strength, as measured by AMPA/NMDA ratios, specifically on direct pathway D1 receptor expressing medium spiny neurons, with no changes on indirect pathway neurons...

Mutant messenger RNA (mRNA) and protein contribute to the clinical manifestation of many repeat-associated neurological disorders, with the presence of nuclear RNA clusters being a common pathological feature. Yet, investigations into Huntington's disease-caused by a CAG repeat expansion in exon 1 of the huntingtin ( HTT ) gene-have primarily focused on toxic protein gain-of-function as the primary disease-causing feature. To date, mutant HTT mRNA has not been identified as an in vivo hallmark of Huntington's disease...

N -methyl-D-aspartate receptors (NMDARs) are important postsynaptic receptors that contribute to normal synaptic function and cell survival; however, when overactivated, as in Huntington's disease (HD), NMDARs cause excitotoxicity. HD-affected striatal neurons show altered NMDAR currents and augmented ratio of surface to internal GluN2B-containing NMDARs, with augmented accumulation at extrasynaptic sites. Fyn protein is a member of the Src kinase family (SKF) with an important role in NMDARs phosphorylation and synaptic localization and function; recently, we demonstrated that Fyn is reduced in several HD models...

Deficits in mitochondrial function and redox deregulation have been attributed to Huntington's disease (HD), a genetic neurodegenerative disorder largely affecting the striatum. However, whether these changes occur in early stages of the disease and can be detected in vivo is still unclear. In the present study, we analysed changes in mitochondrial function and production of reactive oxygen species (ROS) at early stages and with disease progression. Studies were performed in vivo in human brain by PET using [64 Cu]-ATSM and ex vivo in human skin fibroblasts of premanifest and prodromal (Pre-M) and manifest HD carriers...

BACKGROUND: Huntington's disease is a progressive neurodegenerative disorder with no disease-modifying treatments. Patients experience motor, cognitive, and psychiatric disturbances, and the dorsal striatum is the main target of neurodegeneration. Mouse models of Huntington's disease show altered striatal synaptic signaling in vitro, but how these changes relate to behavioral deficits in vivo is unclear. OBJECTIVES: We aimed to investigate how striatal activity correlates with behavior in vivo during motor learning and spontaneous behavior in a Huntington's disease mouse model at two disease stages...

Huntington disease is caused by a CAG repeat expansion in exon 1 of the huntingtin gene (HTT) that is translated into a polyglutamine stretch in the huntingtin protein (HTT). We previously showed that HTT mRNA carrying an expanded CAG repeat was incompletely spliced to generate HTT1a, an exon 1 only transcript, which was translated to produce the highly aggregation-prone and pathogenic exon 1 HTT protein. This occurred in all knock-in mouse models of Huntington's disease and could be detected in patient cell lines and post-mortem brains...

Huntington's disease (HD) is a genetic neurodegenerative disease characterized by motor, psychiatric, and cognitive symptoms. Emerging evidence suggests that emotional and cognitive deficits seen in HD may be related to hippocampal dysfunction. We used the YAC128 HD mouse model to perform a temporal characterization of the behavioral and hippocampal dysfunctions. Early and late symptomatic YAC128 mice exhibited depressive-like behavior, as demonstrated by increased immobility times in the Tail Suspension Test...

Aberrant localization of proteins to mitochondria disturbs mitochondrial function and contributes to the pathogenesis of Huntington's disease (HD). However, the crucial factors and the molecular mechanisms remain elusive. Here, we found that heat shock transcription factor 1 (HSF1) accumulates in the mitochondria of HD cell models, a YAC128 mouse model, and human striatal organoids derived from HD induced pluripotent stem cells (iPSCs). Overexpression of mitochondria-targeting HSF1 (mtHSF1) in the striatum causes neurodegeneration and HD-like behavior in mice...

Among the many proposed therapeutic strategies for Huntington's disease (HD), allele-selective therapies are the most desirable but also the most challenging. RNA interference (RNAi) tools that target CAG repeats selectively reduce the mutant huntingtin level in cellular models of HD. The purpose of this study was to test the efficacy, selectivity, and safety of two vector-based RNAi triggers in an animal model of HD. CAG repeat-targeting short hairpin RNA (shRNA) and artificial miRNA (amiRNA) were delivered to the brains of YAC128 mice via intrastriatal injection of AAV5 vectors...

Almost all Huntington's Disease (HD) patients die within 10-30 years after symptom onset and currently there are no available treatments to slow, stop, or reverse its progression. HD is a neurodegenerative disease that causes a biphasic signaling pattern in the striatum in which there is hyperactive signaling during the early stages, followed by hypoactive signaling later on. Among the many neurotransmitters shown to follow the biphasic signaling pattern found in HD, dopamine (DA) and its inputs from the mid-brain to the striatum are thought to be critical for motor and action planning...