Early and progressive circadian abnormalities in Huntington's disease sheep are unmasked by social environment

Morton, A. Jennifer; Rudiger, Skye R.; Wood, Nigel I.; Sawiak, Stephen J.; Brown, G. A.; McLaughlan, Clive J.; Kuchel, Timothy R.; Snell, Russell G.; Faull, Richard L.M.; Bawden, C. Simon

doi:10.1093/hmg/ddu047

Cited by 81 publications

(74 citation statements)

References 40 publications

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“…The OVT73 sheep display some of the neuropathological changes that occur in HD, including the accumulation of intracellular huntingtin-positive inclusions (18). An alteration in circadian rhythm has been observed, a behavioral phenotype consistent with an early phase in the disease (19). We have also found that levels of specific metabolites are altered in the OVT73 sheep brain and liver.…”

Section: Significancesupporting

confidence: 64%

“…The OVT73 sheep is the only large animal model that expresses full-length mutant (73 glutamines) human huntingtin (17). The OVT73 sheep are considered a prodromal model system since they display no overt symptoms of the disease or cell loss (19), despite the presence of a recognized pathologic correlate, namely huntingtin-positive aggregates (18), as well as altered metabolite levels (20), and a circadian rhythm disruption measurable by Global Positioning System tracking (19). Comparing urea changes in the postmortem brains of the prodromal OVT73 sheep model and endstage HD individuals, our results also suggest that the urea phenotype may be progressive.…”

Section: Discussionmentioning

confidence: 99%

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

Handley

Reid

Bräuning

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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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.is a dominantly inherited neurological disorder typified by chorea, psychological disturbance, and dementia. The symptoms progress and result in premature death, typically 10-15 y after onset. Currently no available treatment can delay or prevent the onset of HD. The gene responsible, Huntingtin (HTT), is ubiquitously expressed and encodes the large and multifunctional huntingtin protein.The disease-causing mutation is an expanded CAG repeat in exon 1 of HTT, coding for a glutamine tract within the protein (1). The disease-causing repeat lower length threshold is 36 units and is fully penetrant at 40 units and above (2, 3). There is an inverse correlation between expanded CAG repeat size and age at onset of symptoms (4-6). Although the mutation is well defined, the pathogenic process is not sufficiently understood to enable effective treatment. The majority of HD research focuses on the brain where there is characteristic neuropathology, primarily atrophy of the striatum (7).Alongside the striking neurological phenotype of HD, there is a generalized metabolic disruption. HD mutation carriers weigh less on average than non-HD individuals (8). Weight loss begins presymptomatically (9, 10), and in symptomatic individuals, energy expenditure far exceeds that utilized in movement, despite high calor...

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Section: Significancesupporting

confidence: 64%

Section: Discussionmentioning

confidence: 99%

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

Handley

Reid

Bräuning

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…Similar observations were also made in R6/2 mouse model [75] and ovine model of HD [76]. Mutated Htt action and loss of wild-type Htt function affect not only the brain structures, but also peripheral tissues or organ systems like testes, heart, pancreas, skeletal muscle, etc.…”

Section: Telemetrysupporting

confidence: 75%

Porcine Model of Huntington's Disease

Rausova¹,

Vochozková²,

Vidinská³

et al. 2017

Huntington's Disease - Molecular Pathogenesis and Current Models

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At present, we are probably the only research facility to be breeding transgenic Huntington's disease minipigs (TgHD). These minipigs express N-terminal part of human mutated huntingtin including 124Q under the control of human huntingtin promoter. The founder animal, born in 2009, gave birth to four subsequent generations with an equal contribution of wild-type (WT) and transgenic (TgHD) piglets in all litters. We take different approaches, some of which are unique for large animal models, to study the phenotype development comparing WT and TgHD siblings. In this chapter, we review these approaches and the phenotype progression in the minipigs. Additionally, we outline perspectives in generation of new models using novel methodology and the potential of pig models in preclinical HD studies.

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“…Along with each dataset, the genotype and background strain are available as a spreadsheet and listed on the website. Full details of the animals and the scan sequences used are described in Sawiak et al (2012) and Morton et al (2014). Typical images are shown in Fig.…”

Section: Repository Detailsmentioning

confidence: 99%

“…Recently an ovine model of HD has been assessed with MRI (Morton et al, 2014) and we are currently adding ovine datasets to our online data repository to supplement the mouse data.…”

Section: Introductionmentioning

confidence: 99%

The Cambridge MRI database for animal models of Huntington disease

Sawiak

Morton

2016

NeuroImage

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We describe the Cambridge animal brain magnetic resonance imaging repository comprising 400 datasets to date from mouse models of Huntington disease. The data include raw images as well as segmented grey and white matter images with maps of cortical thickness. All images and phenotypic data for each subject are freely-available without restriction from (http://www.dspace.cam.ac.uk/handle/1810/243361/). Software and anatomical population templates optimised for animal brain analysis with MRI are also available from this site.

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Early and progressive circadian abnormalities in Huntington's disease sheep are unmasked by social environment

Cited by 81 publications

References 40 publications

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

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

Porcine Model of Huntington's Disease

The Cambridge MRI database for animal models of Huntington disease

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