Small Molecule Hsp90 Modulator and Neuregulin-induced Peripheral Demyelination

Abstract

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.