title: 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.
authors.affiliation: Department of Neuroscience and Anatomy, College of Medicine, McKnight Brain Institute, University of Florida, Gainesville, Florida 32610, USA.
authors.forename: Sunitha
authors.initials: S
authors.lastname: Rangaraju
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Verrier
authors.forename: Irina
authors.initials: I
authors.lastname: Madorsky
authors.forename: Jessica
authors.initials: J
authors.lastname: Nicks
authors.forename: William A
authors.initials: WA
authors.lastname: Dunn
authors.forename: Lucia
authors.initials: L
authors.lastname: Notterpek
mesh_terms: D000818:Animals; D001343:Autophagy / Q000187:drug effects* / Q000502:physiology; D003711:Demyelinating Diseases / Q000188:drug therapy* / Q000473:pathology; D005260:Female; D055785:Gene Knockdown Techniques; D008297:Male; D051379:Mice; D008818:Mice, Neurologic Mutants; D009186:Myelin Sheath / Q000187:drug effects / Q000473:pathology; D009413:Nerve Fibers, Myelinated / Q000187:drug effects* / Q000473:pathology; D009437:Neuralgia / Q000188:drug therapy* / Q000473:pathology; D009924:Organ Culture Techniques; D020123:Sirolimus / Q000494:pharmacology* / Q000627:therapeutic use*
chemical_list: D020123:Sirolimus