Over-expression of DSCR1 protects against post-ischemic neuronal injury

Brait, Vanessa H., Martin, Katherine R., Corlett, Alicia, Broughton, Brad R. S., Kim, Hyun Ah, Thundyil, John, Drummond, Grant R., Arumugam, Thiruma V., Pritchard, Melanie A. and Sobey, Christopher G. (2012) Over-expression of DSCR1 protects against post-ischemic neuronal injury. PLoS One, 7 10: e47841.1-e47841.8. doi:10.1371/journal.pone.0047841


Author Brait, Vanessa H.
Martin, Katherine R.
Corlett, Alicia
Broughton, Brad R. S.
Kim, Hyun Ah
Thundyil, John
Drummond, Grant R.
Arumugam, Thiruma V.
Pritchard, Melanie A.
Sobey, Christopher G.
Total Author Count Override 10
Title Over-expression of DSCR1 protects against post-ischemic neuronal injury
Journal name PLoS One   Check publisher's open access policy
ISSN 1932-6203
Publication date 2012-10-29
Sub-type Article (original research)
DOI 10.1371/journal.pone.0047841
Open Access Status DOI
Volume 7
Issue 10
Start page e47841.1
End page e47841.8
Total pages 8
Place of publication San Francisco, CA, United States
Publisher Public Library of Science
Collection year 2013
Language eng
Formatted abstract
Background and Purpose: The Down syndrome candidate region 1 (DSCR1) gene is located on human chromosome 21 and its protein is over-expressed in brains of Down syndrome individuals. DSCR1 can modulate the activity of calcineurin, a phosphatase abundant in the brain, but its influence on stroke outcome is not clear. We compared stroke outcome in wildtype (WT) and transgenic (DSCR1-TG) mice which over-express isoform 1 of human DSCR1.

Methods: Transient cerebral ischemia was produced by occlusion of the middle cerebral artery for 0.5 h. After 23.5 h reperfusion, we assessed neurological impairment, brain infarct and edema volume, leukocyte infiltration and markers of inflammation. Intrinsic resistance to apoptosis following glucose deprivation was also assessed in primary cultures of WT and DSCR1-TG neurons.

Results:
In contrast to WT, DSCR1-TG mice had an improved neurological deficit score, greater grip strength, attenuated infarct volume and brain swelling, and lacked hippocampal lesions after stroke. Expression of mouse DSCR1-1, but not DSCR1-4, mRNA and protein was increased by ischemia in both WT and DSCR1-TG. Brain calcineurin activity was increased to a similar degree after ischemia in each genotype. DSCR1-TG mice had fewer infiltrating neutrophils and activated microglia compared with WT, in association with an attenuated upregulation of several pro-inflammatory genes. Neurons from DSCR1-TG mice were more resistant than WT neurons to apoptotic cell death following 24 h of glucose deprivation.

Conclusions: Over-expression of DSCR1 in mice improves outcome following stroke. Mechanisms underlying this protection may involve calcineurin-independent, anti-inflammatory and anti-apoptotic effects mediated by DSCR1 in neurons.
Keyword Down syndrome
DSCR1
Calcineurin
Stroke outcome
Transient cerebral ischemi
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ
Additional Notes Published on: 29 October 2012. Article number e47841

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2013 Collection
School of Biomedical Sciences Publications
 
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Created: Thu, 01 Nov 2012, 13:33:38 EST by Dr Thiruma V Arumugam on behalf of School of Biomedical Sciences