Small Molecule Hsp90 Modulator and Neuregulin-induced Peripheral Demyelination

Abstract Modulating molecular chaperones is emerging as an attractive approach to treat neurodegenerative diseases associated with protein aggregation, diabetic peripheral neuropathy (DPN) and possibly, demyelinating neuropathies. KU-32 is a small molecule inhibitor of heat shock protein 90 (Hsp90) and reverses sensory deficits associated with myelinated fiber dysfunction in DPN. Additionally, KU-32 prevented the loss of myelinated internodes induced by treating myelinated Schwann cell-dorsal root ganglia sensory neuron co-cultures with neuregulin-1 Type 1 (NRG1). 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 and induction of the transcription factor c-jun function 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 wild type and Hsp70 KO 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 wildtype (WT) mice. KU-32 did not prevent the NRG1-dependent induction of c-jun and loss of myelin segments in explants from Hsp70 KO mice. Over-expression 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