Induction of heat shock protein 70 (Hsp70) prevents neuregulin-induced demyelination by enhancing the proteasomal clearance of c-Jun
| Autor: | Rick T. Dobrowsky, Brian S. J. Blagg, Jiacheng Ma, Huiping Zhao, Chengyuan Li |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2012 |
| Předmět: |
MAPK/ERK pathway
MBP myelin basic protein NRG1 neuregulin-1 Type 1 Fluorescent Antibody Technique HRP horseradish peroxidise Myelin Mice 0302 clinical medicine Hsc70 heat-shock cognate 70 stress protein Ganglia Spinal CMT1 Charcot–Marie–Tooth disease type 1 pAb polyclonal antibody Schwann cells HS heat shock Mice Knockout 0303 health sciences DMEM Dulbecco's modified Eagle's medium biology Reverse Transcriptase Polymerase Chain Reaction General Neuroscience c-jun molecular chaperones HSR heat shock response S11 diabetic neuropathy 3. Good health medicine.anatomical_structure PBST phosphate-buffered saline containing 0.1% Tween 20 JNK c-Jun N-terminal kinase DPN diabetic peripheral neuropathy Research Article Signal Transduction DAPI 4 6-diamidino-2-phenylindole HSF1 heat shock factor 1 Neuregulin-1 Immunoblotting Schwann cell 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 S3 lcsh:RC321-571 03 medical and health sciences Heat shock protein CHIP C-terminus Hsp70-interacting protein medicine Hsp heat shock protein Animals HSP70 Heat-Shock Proteins Neuregulin 1 mAb monoclonal antibody lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry 030304 developmental biology KO knockout PGP9.5 protein gene product 9.5 PMP22 peripheral myelin protein 22 JNK Mitogen-Activated Protein Kinases phospho-c-Jun phosphorylated c-Jun myelin basic protein Molecular biology WT wild-type Sensory neuron Coculture Techniques Myelin basic protein SC Schwann cell DRG dorsal root ganglia Mice Inbred C57BL sensory neurons biology.protein Neurology (clinical) FCS fetal calf serum 030217 neurology & neurosurgery MAPK mitogen-activated protein kinase Demyelinating Diseases |
| Zdroj: | ASN NEURO ASN Neuro, Vol 4 (2012) |
| ISSN: | 1759-0914 |
| Popis: | Modulating 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-((2 R,3 R,4 S,5 R)-3,4-dihydroxy-5-methoxy-6,6-dimethyl-tetrahydro-2 H-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. |
| Databáze: | OpenAIRE |
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