Rapamycin Activates Autophagy and Improves Myelination in Explant Cultures from Neuropathic Mice

Abstract

Misexpression and cytosolic retention of peripheral myelin protein 22 (PMP22) within Schwann cells (SCs) is associated with a genetically heterogeneous group of demyelinating peripheral neuropathies. PMP22 overproducer C22 and spontaneous mutant Trembler J (TrJ) mice display neuropathic phenotypes and affected nerves contain abnormally localized PMP22. Nutrient deprivation-induced autophagy is able to suppress the formation of PMP22 aggregates in a toxin-induced cellular model, and improve locomotor performance and myelination in TrJ mice. As a step toward therapies, we assessed whether pharmacological activation of autophagy by rapamycin (RM) could facilitate the processing of PMP22 within neuropathic SCs and enhance their capacity to myelinate peripheral axons. Exposure of mouse SCs to RM induced autophagy in a dose- and time-dependent manner and decreased the accumulation of poly-ubiquitinated substrates. The treatment of myelinating dorsal root ganglion (DRG) explant cultures from neuropathic mice with RM (25 nM) improved the processing of PMP22 and increased the abundance and length of myelin internodes, as well as the expression of myelin proteins. Notably, RM is similarly effective in both the C22 and TrJ model, signifying that the benefit overlaps among distinct genetic models of PMP22 neuropathies. Furthermore, lentivirus-mediated shRNA knockdown of the autophagy-related gene 12 (Atg12) abolished the activation of autophagy and the increase in myelin proteins, demonstrating that autophagy is critical for the observed improvement. Together, these results support the potential use of RM and other autophagy-enhancing compounds as therapeutic agents for PMP22-associated demyelinating neuropathies.

Expression pattern and functions of autophagy-related geneatg5in zebrafish organogenesis

“…In view of rapamycin as a reagent for autophagy induction, 27,28 we probed whether rapamycin can impact zebrafish embryonic development and atg5 expression. The results showed that the rapamycintreated embryos presented the similar immature phenotype (Fig.…”

Mutations associated with Charcot–Marie–Tooth disease cause SIMPLE protein mislocalization and degradation by the proteasome and aggresome–autophagy pathways

“…Together, our data support the involvement of the aggresome-autophagy pathway in the degradation of SIMPLE mutant proteins. Interestingly, aggresomes were also found in Schwann cells expressing misfolded PMP22 mutant proteins (Ryan et al, 2002;Fortun et al, 2006) and pharmacological activation of autophagy by rapamycin was shown to improve myelination in PMP22 mutant mice (Rangaraju et al, 2010). Thus, augmentation of the aggresome-autophagy pathway might be a viable therapeutic strategy for treating a number of demyelinating neuropathies.…”

Role of Autophagy in Early Brain Injury after Experimental Subarachnoid Hemorrhage

“…Tor forms two functionally distinct protein complexes, Tor complex 1 and 2 (TORC1 and TORC2), and TORC1 has the primary role in regulating autophagy. Under nutrient-rich conditions, TORC1 is active and inhibits autophagy, whereas TORC1 is inhibited upon nutrient deprivation, allowing an increase in autophagic activity (Rangaraju et al 2010). As mentioned by Nührenberg et al (2005), besides the modulating effect of autophagy pathway, rapamycin has profound inhibitory influence on the proinflammatory gene expression pattern and on promoters of hematopoetic progenitor cells (HPC) after vascular injury.…”