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dc.contributor.authorLi, Chengyuan
dc.contributor.authorMa, Jiacheng
dc.contributor.authorZhao, Huiping
dc.contributor.authorBlagg, Brian S. J.
dc.contributor.authorDobrowsky, Rick T.
dc.date.accessioned2015-05-08T18:20:19Z
dc.date.available2015-05-08T18:20:19Z
dc.date.issued2012-11-01
dc.identifier.citationLi, Chengyuan, Jiacheng Ma, Huiping Zhao, Brian S.J. Blagg, and Rick T. Dobrowsky. "Induction of Heat Shock Protein 70 (Hsp70) prevents Neuregulin-Induced Demyelination by Enhancing the Proteasomal Clearance of c-Jun." ASN Neuro November 2012 vol. 4 no. 7 20120047.

http://dx.doi.org/10.1042/20120047
en_US
dc.identifier.urihttp://hdl.handle.net/1808/17661
dc.description.abstractModulating molecular chaperones is emerging as an attractive approach to treat neurodegenerative diseases associated with protein aggregation, DPN (diabetic peripheral neuropathy) and possibly, demyelinating neuropathies. KU-32 [N-(7-((2R,3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyl-tetrahydro-2H-pyran-2-yloxy)-8-methyl-2-oxo-2H-chromen-3-yl)acetamide] is a small molecule inhibitor of Hsp90 (heat shock protein 90) and reverses sensory deficits associated with myelinated fibre dysfunction in DPN. Additionally, KU-32 prevented the loss of myelinated internodes induced by treating myelinated SC (Schwann cell)-DRG (dorsal root ganglia) sensory neuron co-cultures with NRG1 (neuregulin-1 Type 1). Since KU-32 decreased NRG1-induced demyelination in an Hsp70-dependent manner, the goal of the current study was to clarify how Hsp70 may be mechanistically linked to preventing demyelination. The activation of p42/p44 MAPK (mitogen-activated protein kinase) and induction of the transcription factor c-Jun serve as negative regulators of myelination. NRG1 activated MAPK, induced c-Jun expression and promoted a loss of myelin segments in DRG explants isolated from both WT (wild-type) and Hsp70 KO (knockout) mice. Although KU-32 did not block the activation of MAPK, it blocked c-Jun induction and protected against a loss of myelinated segments in WT mice. In contrast, KU-32 did not prevent the NRG1-dependent induction of c-Jun and loss of myelin segments in explants from Hsp70 KO mice. Overexpression of Hsp70 in myelinated DRG explants prepared from WT or Hsp70 KO mice was sufficient to block the induction of c-Jun and the loss of myelin segments induced by NRG1. Lastly, inhibiting the proteasome prevented KU-32 from decreasing c-Jun levels. Collectively, these data support that Hsp70 induction is sufficient to prevent NRG1-induced demyelination by enhancing the proteasomal degradation of c-Jun.en_US
dc.description.sponsorshipThis work was supported the Juvenile Diabetes Research Foundation and The National Institutes of Health [grant numbers NS054847 (to R.T.D.), CA120458 and CA109265 (to B.S.J.B.) and NS075311 (to B.S.J.B. and R.T.D.)].en_US
dc.publisherSAGEen_US
dc.rightsThis is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial Licence (http://creativecommons.org/licenses/by-nc/2.5/) which permits unrestricted non-commercial use, distribution and reproduction in any medium, provided the original work is properly cited.
dc.rights.urihttp://creativecommons.org/licenses/by-nc/2.5/
dc.subjectDiabetic neuropathyen_US
dc.subjectMolecular chaperonesen_US
dc.subjectMyelin basic proteinen_US
dc.subjectSchwann cellsen_US
dc.subjectSensory neuronsen_US
dc.titleInduction of Heat Shock Protein 70 (Hsp70) prevents Neuregulin-Induced Demyelination by Enhancing the Proteasomal Clearance of c-Junen_US
dc.typeArticle
kusw.kuauthorLi, Chengyuan
kusw.kuauthorMa, Jiacheng
kusw.kuauthorZhao, Huiping
kusw.kuauthorBlagg, Brian S. J.
kusw.kudepartmentDepartment of Medicinal Chemistyen_US
dc.identifier.doi10.1042/20120047
kusw.oaversionScholarly/refereed, publisher version
kusw.oapolicyThis item meets KU Open Access policy criteria.
dc.rights.accessrightsopenAccess


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This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial Licence (http://creativecommons.org/licenses/by-nc/2.5/) which permits unrestricted non-commercial use, distribution and reproduction in any medium, provided the original work is properly cited.
Except where otherwise noted, this item's license is described as: This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial Licence (http://creativecommons.org/licenses/by-nc/2.5/) which permits unrestricted non-commercial use, distribution and reproduction in any medium, provided the original work is properly cited.