dc.contributor.author |
Handley, Renee |
en |
dc.contributor.author |
Reid, Susanne |
en |
dc.contributor.author |
Brauning, Rudiger |
en |
dc.contributor.author |
Maclean, Paul |
en |
dc.contributor.author |
Mears, Emily |
en |
dc.contributor.author |
Fourie, Imche |
en |
dc.contributor.author |
Patassini, Stefano |
en |
dc.contributor.author |
Cooper, Garth |
en |
dc.contributor.author |
Rudiger, Skye R |
en |
dc.contributor.author |
McLaughlan, Clive J |
en |
dc.contributor.author |
Verma, Paul J |
en |
dc.contributor.author |
Gusella, James F |
en |
dc.contributor.author |
MacDonald, Marcy E |
en |
dc.contributor.author |
Waldvogel, Henry |
en |
dc.contributor.author |
Bawden, C Simon |
en |
dc.contributor.author |
Faull, Richard |
en |
dc.contributor.author |
Snell, Russell |
en |
dc.date.accessioned |
2018-11-21T23:40:10Z |
en |
dc.date.issued |
2017-12-11 |
en |
dc.identifier.citation |
Proceedings of the National Academy of Sciences of the United States of America 114(52):E11293-E11302 2017 |
en |
dc.identifier.issn |
0027-8424 |
en |
dc.identifier.uri |
http://hdl.handle.net/2292/44551 |
en |
dc.description.abstract |
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. |
en |
dc.format.medium |
Print-Electronic |
en |
dc.language |
eng |
en |
dc.relation.ispartofseries |
Proceedings of the National Academy of Sciences of the United States of America |
en |
dc.rights |
Items in ResearchSpace are protected by copyright, with all rights reserved, unless otherwise indicated. Previously published items are made available in accordance with the copyright policy of the publisher. |
en |
dc.rights.uri |
https://researchspace.auckland.ac.nz/docs/uoa-docs/rights.htm |
en |
dc.rights.uri |
https://creativecommons.org/licenses/by-nc-nd/4.0/ |
en |
dc.subject |
Corpus Striatum |
en |
dc.subject |
Animals |
en |
dc.subject |
Animals, Genetically Modified |
en |
dc.subject |
Sheep |
en |
dc.subject |
Humans |
en |
dc.subject |
Huntington Disease |
en |
dc.subject |
Disease Models, Animal |
en |
dc.subject |
Urea |
en |
dc.subject |
Trinucleotide Repeat Expansion |
en |
dc.subject |
Adult |
en |
dc.subject |
Female |
en |
dc.subject |
Male |
en |
dc.subject |
Huntingtin Protein |
en |
dc.title |
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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dc.type |
Journal Article |
en |
dc.identifier.doi |
10.1073/pnas.1711243115 |
en |
pubs.issue |
52 |
en |
pubs.begin-page |
E11293 |
en |
pubs.volume |
114 |
en |
dc.rights.holder |
Copyright: The authors |
en |
dc.identifier.pmid |
29229845 |
en |
pubs.end-page |
E11302 |
en |
pubs.publication-status |
Published |
en |
dc.rights.accessrights |
http://purl.org/eprint/accessRights/OpenAccess |
en |
pubs.subtype |
Research Support, Non-U.S. Gov't |
en |
pubs.subtype |
research-article |
en |
pubs.subtype |
Journal Article |
en |
pubs.elements-id |
719157 |
en |
pubs.org-id |
Medical and Health Sciences |
en |
pubs.org-id |
Medical Sciences |
en |
pubs.org-id |
Anatomy and Medical Imaging |
en |
pubs.org-id |
Science |
en |
pubs.org-id |
Biological Sciences |
en |
pubs.org-id |
Science Research |
en |
pubs.org-id |
Maurice Wilkins Centre (2010-2014) |
en |
dc.identifier.eissn |
1091-6490 |
en |
pubs.record-created-at-source-date |
2017-12-13 |
en |
pubs.dimensions-id |
29229845 |
en |