气候变化领域集成服务门户(CCPortal): Brain urea increase is an early Huntington's disease pathogenic event observed in a prodromal transgenic sheep model and HD cases

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DOI	10.1073/pnas.1711243115
	Brain urea increase is an early Huntington's disease pathogenic event observed in a prodromal transgenic sheep model and HD cases
	Handley R.R.; Reid S.J.; Brauning R.; MacLean P.; Mears E.R.; Fourie I.; Patassini S.; Cooper G.J.S.; Rudiger S.R.; McLaughlan C.J.; Verma P.J.; Gusella J.F.; MacDonald M.E.; Waldvogel H.J.; Bawden C.S.; Faull R.L.M.; Snell R.G.
发表日期	2017
ISSN	0027-8424
起始页码	E11293
结束页码	E11302
卷号	114 期号:52
英文摘要	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.
英文关键词	Huntington's disease; Metabolism; Prodromal; Sheep; Urea
语种	英语
scopus关键词	ammonia; complementary DNA; huntingtin; urea; HTT protein, human; huntingtin; urea; animal experiment; animal model; Article; cerebellum; controlled study; corpus striatum; energy resource; female; gene expression; human; human tissue; Huntington chorea; male; metabolite; neuropathology; nonhuman; osmosis; priority journal; protein degradation; RNA sequence; striate cortex; transgenic sheep; adult; animal; disease model; genetics; Huntington chorea; metabolism; pathology; sheep; transgenic animal; trinucleotide repeat; Adult; Animals; Animals, Genetically Modified; Corpus Striatum; Disease Models, Animal; Female; Humans; Huntingtin Protein; Huntington Disease; Male; Sheep; Trinucleotide Repeat Expansion; Urea
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/160560
作者单位	Handley, R.R., Centre for Brain Research, School of Biological Sciences, University of Auckland, Auckland, 1010, New Zealand; Reid, S.J., Centre for Brain Research, School of Biological Sciences, University of Auckland, Auckland, 1010, New Zealand; Brauning, R., Invermay Agricultural Centre, AgResearch Ltd., Mosgiel, 9053, New Zealand; MacLean, P., Invermay Agricultural Centre, AgResearch Ltd., Mosgiel, 9053, New Zealand; Mears, E.R., Centre for Brain Research, School of Biological Sciences, University of Auckland, Auckland, 1010, New Zealand; Fourie, I., Centre for Brain Research, School of Biological Sciences, University of Auckland, Auckland, 1010, New Zealand; Patassini, S., Centre for Brain Research, Faculty of Medical and Health Science, University of Auckland, Auckland, 1023, New Zealand, Centre for Advanced Discovery and Experimental Therapeutics, Division of Cardiovascular Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, M13 9PL,...
推荐引用方式 GB/T 7714	Handley R.R.,Reid S.J.,Brauning R.,et al. Brain urea increase is an early Huntington's disease pathogenic event observed in a prodromal transgenic sheep model and HD cases[J],2017,114(52).
APA	Handley R.R..,Reid S.J..,Brauning R..,MacLean P..,Mears E.R..,...&Snell R.G..(2017).Brain urea increase is an early Huntington's disease pathogenic event observed in a prodromal transgenic sheep model and HD cases.Proceedings of the National Academy of Sciences of the United States of America,114(52).
MLA	Handley R.R.,et al."Brain urea increase is an early Huntington's disease pathogenic event observed in a prodromal transgenic sheep model and HD cases".Proceedings of the National Academy of Sciences of the United States of America 114.52(2017).