Pharmacological induction of the heat shock response improves myelination in a neuropathic model

Abstract

Misexpression and intracellular retention of peripheral myelin protein 22 (PMP22) is associated with hereditary neuropathies in humans, including Charcot-Marie-Tooth disease type 1A (CMT1A). Mice expressing extra copies of the human PMP22, termed C22, display morphologic and behavioral characteristics of CMT1A. In neuropathic Schwann cells, the turnover of the newly-synthesized PMP22 is decreased, leading to the formation of cytosolic protein aggregates. To aid the processing of PMP22 and alleviate the associated myelin defects, we pharmacologically stimulated the expression of protein chaperones by synthetic small-molecule inhibitors of heat shock protein 90 (HSP90). The exposure of Schwann cells to these compounds enhanced the levels of cytosolic chaperones in a time- and dose-dependent manner, with minimal cytotoxicity. Treatment of dorsal root ganglion (DRG) explants from neuropathic mice improved myelin formation and the processing of PMP22. These results warrant further studies with HSP90 inhibitors as potential therapeutic candidates for hereditary demyelinating neuropathies.

Promoting peripheral myelin repair

“…The entrapment of chaperones in protein aggregates led to attempts to enhance chaperone production in multiple neurodegenerative disease models through inhibition of HSP90 (Lindberg et al, 2015). Indeed, the induction of HSP70 and other chaperones prevents the aggregation of the mutated or overproduced PMP22 and is beneficial for myelination (Chittoor-Vinod et al, 2015; Rangaraju et al, 2008). Interestingly, modulation of chaperones is also beneficial in rodent models of diabetic neuropathies (Ma et al, 2015), which supports the notion that this pathway is suitable for development in PNS disorders and injury.…”

Resetting translational homeostasis restores myelination in Charcot-Marie-Tooth disease type 1B mice

“…Autophagy, stimulated via fasting or rapamycin, or an increase in the heat shock response, can improve the phenotype of some PMP22-related neuropathies (Fortun et al, 2007;Rangaraju et al, 2008Rangaraju et al, , 2010Madorsky et al, 2009), and salubrinal enhancement of the integrated stress response (ISR) ameliorated hypomyelination and oligodendrocyte loss in cultured hippocampal slices exposed to IFN- (Lin et al, 2008).…”

Chaperoning erythropoiesis

“…Modulation of molecular chaperone activity in neurons by small molecules or gene transfer can suppress aggregation and stimulate degradation of the offending protein, enhancing neuronal survival in cultured cells and in whole organisms. 22,[137][138][139][140][141][142][143][144][145] It may even be possible to dissolve protein aggregates in mammalian cells by ectopic expression of the Hsp 104, which is normally expressed only in lower organisms. 146 Similar approaches should be applicable to the treatment of erythroid disorders such as thalassemia where accumulation and precipitation of unstable globin proteins play a predominant role in disease pathophysiology.…”