| First Author | Zhang X | Year | 2018 |
| Journal | ACS Chem Neurosci | Volume | 9 |
| Issue | 2 | Pages | 381-390 |
| PubMed ID | 29120605 | Mgi Jnum | J:361457 |
| Mgi Id | MGI:7857013 | Doi | 10.1021/acschemneuro.7b00377 |
| Citation | Zhang X, et al. (2018) Targeting Heat Shock Protein 70 to Ameliorate c-Jun Expression and Improve Demyelinating Neuropathy. ACS Chem Neurosci 9(2):381-390 |
| abstractText | Increased expression of the c-jun transcription factor occurs in a variety of human neuropathies and is critical in promoting Schwann cell (SC) dedifferentiation and loss of the myelinated phenotype. Using cell culture models, we previously identified KU-32 as a novobiocin-based C-terminal heat shock protein 90 (Hsp90) inhibitor that decreased c-jun expression and the extent of demyelination. Additional chemical optimization has yielded KU-596 as a neuroprotective novologue whose mechanistic efficacy to improve a metabolic neuropathy requires the expression of Hsp70. The current study examined whether KU-596 therapy could decrease c-jun expression and improve motor function in an inducible transgenic model of a SC-specific demyelinating neuropathy (MPZ-Raf mice). Treating MPZ-Raf mice with tamoxifen activates the MAPK kinase pathway, increases c-jun expression and produces a profound demyelinating neuropathy characterized by a loss of motor function and paraparesis. KU-596 therapy did not interfere with MAPK activation but reduced c-jun expression, significantly improved motor performance, and ameliorated the extent of peripheral nerve demyelination in both prevention and intervention studies. Hsp70 was necessary for the drug's neuroprotective efficacy since MPZ-Raf x Hsp70 knockout mice did not respond to KU-596 therapy. Collectively, our data indicate that modulating Hsp70 may provide a novel therapeutic approach to attenuate SC c-jun expression and ameliorate the onset of certain demyelinating neuropathies in humans. |
