Further Molecular Characterisation of the OVT73 Transgenic Sheep Model of Huntington's Disease Identifies Cortical Aggregates

2013 ◽  
Vol 2 (3) ◽  
pp. 279-295 ◽  
Author(s):  
◽  
Suzanne J. Reid ◽  
Stefano Patassini ◽  
Renée R. Handley ◽  
Skye R. Rudiger ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Molecular Characterisation ◽  
Sheep Model ◽  
Transgenic Sheep

scholarly journals DNA methylation study of Huntington’s disease and motor progression in patients and in animal models

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Ake T. Lu ◽  
Pritika Narayan ◽  
Matthew J. Grant ◽  
Peter Langfelder ◽  
Nan Wang ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Genetic Disorder ◽  
Mammalian Species ◽  
Motor Score ◽  
Sheep Model ◽  
Mutation Status ◽  
Clinical Assessments ◽  
Transgenic Sheep

Abstract 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) and in the transgenic sheep model (p = 2.4 × 10−88). We define a measure of HD motor score progression among manifest HD cases based on multiple clinical assessments. EWAS of motor progression in manifest HD cases exhibits significant (p < 10−7) associations with methylation levels at three loci: near PEX14 (p = 9.3 × 10−9), GRIK4 (p = 3.0 × 10−8), and COX4I2 (p = 6.5 × 10−8). We conclude that HD is accompanied by profound changes of DNA methylation levels in three mammalian species.

scholarly journals Metabolic disruption identified in the Huntington’s disease transgenic sheep model

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Renee. R. Handley ◽  
Suzanne J. Reid ◽  
Stefano Patassini ◽  
Skye R. Rudiger ◽  
Vladimir Obolonkin ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Sheep Model ◽  
Transgenic Sheep ◽  
Metabolic Disruption

scholarly journals Artificial miRNAs Reduce Human Mutant Huntingtin Throughout the Striatum in a Transgenic Sheep Model of Huntington's Disease

2018 ◽  
Vol 29 (6) ◽  
pp. 663-673 ◽  
Author(s):  
Edith L. Pfister ◽  
Natalie DiNardo ◽  
Erica Mondo ◽  
Florie Borel ◽  
Faith Conroy ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Mutant Huntingtin ◽  
Sheep Model ◽  
Transgenic Sheep

scholarly journals A Multi-omic Huntington’s Disease Transgenic Sheep-Model Database for Investigating Disease Pathogenesis

2021 ◽  
pp. 1-12
Author(s):  
Emily R. Mears ◽  
Renee R. Handley ◽  
Matthew J. Grant ◽  
Suzanne J. Reid ◽  
Benjamin T. Day ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Model Systems ◽  
Sheep Model ◽  
Tissue Samples ◽  
Proteomic Data ◽  
Alternate Model ◽  
Model Database ◽  
User Friendly ◽  
And Control

Background: The pathological mechanism of cellular dysfunction and death in Huntington’s disease (HD) is not well defined. Our transgenic HD sheep model (OVT73) was generated to investigate these mechanisms and for therapeutic testing. One particular cohort of animals has undergone focused investigation resulting in a large interrelated multi-omic dataset, with statistically significant changes observed comparing OVT73 and control ‘omic’ profiles and reported in literature. Objective: Here we make this dataset publicly available for the advancement of HD pathogenic mechanism discovery. Methods: To enable investigation in a user-friendly format, we integrated seven multi-omic datasets from a cohort of 5-year-old OVT73 (n = 6) and control (n = 6) sheep into a single database utilising the programming language R. It includes high-throughput transcriptomic, metabolomic and proteomic data from blood, brain, and other tissues. Results: We present the ‘multi-omic’ HD sheep database as a queriable web-based platform that can be used by the wider HD research community (https://hdsheep.cer.auckland.ac.nz/). The database is supported with a suite of simple automated statistical analysis functions for rapid exploratory analyses. We present examples of its use that validates the integrity relative to results previously reported. The data may also be downloaded for user determined analysis. Conclusion: We propose the use of this online database as a hypothesis generator and method to confirm/refute findings made from patient samples and alternate model systems, to expand our understanding of HD pathogenesis. Importantly, additional tissue samples are available for further investigation of this cohort.

scholarly journals Abnormally abrupt transitions from sleep-to-wake in Huntington’s disease sheep (Ovis aries) are revealed by automated analysis of sleep/wake transition dynamics

PLoS ONE ◽  
2021 ◽  
Vol 16 (5) ◽  
pp. e0251767
Author(s):  
William T. Schneider ◽  
Szilvia Vas ◽  
Alister U. Nicol ◽  
A. Jennifer Morton
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Slow Wave ◽  
Early Stage ◽  
Automated Analysis ◽  
Ovis Aries ◽  
Wave Power ◽  
Sheep Model ◽  
Transition Dynamics ◽  
Sleep Abnormalities

Sleep disturbance is a common and disruptive symptom of neurodegenerative diseases such as Alzheimer’s and Huntington’s disease (HD). In HD patients, sleep fragmentation appears at an early stage of disease, although features of the earliest sleep abnormalities in presymptomatic HD are not fully established. Here we used novel automated analysis of quantitative electroencephalography to study transitions between wake and non-rapid eye movement sleep in a sheep model of presymptomatic HD. We found that while the number of transitions between sleep and wake were similar in normal and HD sheep, the dynamics of transitions from sleep-to-wake differed markedly between genotypes. Rather than the gradual changes in EEG power that occurs during transitioning from sleep-to-wake in normal sheep, transition into wake was abrupt in HD sheep. Furthermore, transitions to wake in normal sheep were preceded by a significant reduction in slow wave power, whereas in HD sheep this prior reduction in slow wave power was far less pronounced. This suggests an impaired ability to prepare for waking in HD sheep. The abruptness of awakenings may also have potential to disrupt sleep-dependent processes if they are interrupted in an untimely and disjointed manner. We propose that not only could these abnormal dynamics of sleep transitions be useful as an early biomarker of HD, but also that our novel methodology would be useful for studying transition dynamics in other sleep disorders.

scholarly journals Brain urea increase is an early Huntington’s disease pathogenic event observed in a prodromal transgenic sheep model and HD cases

2017 ◽  
Vol 114 (52) ◽  
pp. E11293-E11302 ◽  
Author(s):  
Renee R. Handley ◽  
Suzanne J. Reid ◽  
Rudiger Brauning ◽  
Paul Maclean ◽  
Emily R. Mears ◽  
...  
Keyword(s):  
Human Brain ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Neurodegenerative Disorder ◽  
Cag Repeat ◽  
Causative Mutation ◽  
Striatal Neurons ◽  
Psychological Disturbance ◽  
Postmortem Human Brain ◽  
Sheep Model

The neurodegenerative disorder Huntington’s disease (HD) is typically characterized by extensive loss of striatal neurons and the midlife onset of debilitating and progressive chorea, dementia, and psychological disturbance. HD is caused by a CAG repeat expansion in the Huntingtin (HTT) gene, translating to an elongated glutamine tract in the huntingtin protein. The pathogenic mechanism resulting in cell dysfunction and death beyond the causative mutation is not well defined. To further delineate the early molecular events in HD, we performed RNA-sequencing (RNA-seq) on striatal tissue from a cohort of 5-y-old OVT73-line sheep expressing a human CAG-expansion HTT cDNA transgene. Our HD OVT73 sheep are a prodromal model and exhibit minimal pathology and no detectable neuronal loss. We identified significantly increased levels of the urea transporter SLC14A1 in the OVT73 striatum, along with other important osmotic regulators. Further investigation revealed elevated levels of the metabolite urea in the OVT73 striatum and cerebellum, consistent with our recently published observation of increased urea in postmortem human brain from HD cases. Extending that finding, we demonstrate that postmortem human brain urea levels are elevated in a larger cohort of HD cases, including those with low-level neuropathology (Vonsattel grade 0/1). This elevation indicates increased protein catabolism, possibly as an alternate energy source given the generalized metabolic defect in HD. Increased urea and ammonia levels due to dysregulation of the urea cycle are known to cause neurologic impairment. Taken together, our findings indicate that aberrant urea metabolism could be the primary biochemical disruption initiating neuropathogenesis in HD.

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