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    Modulating Molecular Chaperones to Treat Demyelinating Neuropathies

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    Available after: 2020-05-31 (6.238Mb)
    Issue Date
    2018-08-31
    Author
    Zhang, Xinyue
    Publisher
    University of Kansas
    Format
    131 pages
    Type
    Dissertation
    Degree Level
    Ph.D.
    Discipline
    Pharmacology & Toxicology
    Rights
    Copyright held by the author.
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    Abstract
    Peripheral neuropathies can be classified into two categories, demyelinating or axonal neuropathy. Demyelinating neuropathies are characterized by damaged myelin but intact axons. Recent evidence suggests that the leucine zipper transcription factor c-jun is at the center of driving demyelination. c-Jun is required for Schwann cells (SCs) to dedifferentiate after injury, and up-regulation of c-jun has been reported in human neuropathies. It remains to be tested whether c-jun would be a valid target for treating demyelinating neuropathies. Previously, our published work has shown that modulating the expression of heat shock protein 70 (Hsp70) using a novel small molecule drug called KU-32 attenuated the expression of c-jun and the extent of demyelination in SC-dorsal root ganglia (DRG) co-cultures in an Hsp70 dependent manner. To extend these data, this work examined the in vivo effects of modulating molecular chaperones using the next generation novologue KU-596 in two mouse models of demyelinating neuropathies. MPZ-Raf mice are a conditional transgenic mouse line that exhibits a demyelinating neuropathy due to the SC-specific induction of mitogen-activated protein kinase (MAPK) and c-jun induction after tamoxifen (TMX) injections in adult mice. Five days of TMX treatment induced a severe motor deficits starting from day 8 and treating the MPZ-Raf mice with 20 mg/kg of KU-596 every other day reduced c-jun levels in the sciatic nerves. The decrease in c-jun correlated with an improvement in the myelination status of the nerves and motor function. In line with previous findings, the effects of KU-596 were Hsp70-dependent, as MPZ-RAF × Hsp70 knockout (KO) mice did not show improvement following drug treatment. This study provides proof of principal that modulating molecular chaperones would be beneficial in treating demyelinating neuropathies. However, as this model is less relevant to an actual disease, we complemented our study using a model of human X-linked Charcot-Marie-Tooth disease (CMT1X). CMT1X is caused by the mutation of gap junction beta 1 gene (GJB1) that encodes the gap junction protein connexin 32 (Cx32). Recent evidence suggests an elevated c-jun expression is associated with the disease. Since c-jun could promote demyelination, targeting c-jun using KU-596 could provide a potential therapeutic strategy to treat CMT1X. The pathology of Cx32 deficient (Cx32def) mice occurs in two stages where young mice develop a pre-demyelinating axonopathy, which progresses to a more severe demyelinating neuropathy in older mice. We show that in young mice that exhibit a pre-demyelinating axonopathy, one-month of KU-596 treatment decreased c-jun expression and improved motor nerve conduction velocity (MNCV) and compound muscle action potential (CMAP). In older Cx32def mice that developed a demyelinating neuropathy, 3 months of KU-596 treatment decreased c-jun expression and improved grip strength, MNCV and CMAP. Hsp70 is required for drug efficacy as neither young nor old Cx32def × Hsp70 KO mice showed improvement following KU-596 treatment. Collectively, our data indicates that modulating molecular chaperones is beneficial in managing demyelinating neuropathies.
    URI
    http://hdl.handle.net/1808/27832
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    • Dissertations [4454]
    • Pharmacy Dissertations and Theses [118]

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    785-864-8983
    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
    785-864-8983

    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
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    Contact KU ScholarWorks
    785-864-8983
    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
    785-864-8983

    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
    Image Credits
     

     

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