Axonal Activation of the Unfolded Protein Response Promotes Axonal Regeneration Following Peripheral Nerve Injury. (1st April 2018)

• Record Type: Journal Article
• Authors: Ohtake, Yosuke; Matsuhisa, Koji; Kaneko, Masayuki; Kanemoto, Soshi; Asada, Rie; Imaizumi, Kazunori; Saito, Atsushi
• Is Part Of: Neuroscience. Volume 375(2018)
• Page Start: 34
• Page End: 48
• Publication Date: 2018-04-01
• Subjects: 2-APB 2-aminoethoxydiphenyl borate -- AD Alzheimer's disease -- ATF6 activating transcription factor 6 -- BiP binding immunoglobulin protein -- BSA bovine serum albumin -- CHOP CCAAT enhancer binding protein homologous protein -- DRG dorsal root ganglion -- EDTA ethylene diamine tetraacetic acid -- EGTA ethylene glycol tetraacetic acid -- eIF2α α subunit of the translation initiation factor -- ER endoplasmic reticulum -- GSK-3β glycogen synthase kinase-3β -- IB immunoblotting -- IF immunofluorescence -- IP3R inositol triphosphate receptor -- IRE1 inositol-requiring kinase endonuclease 1 -- PD Parkinson's disease -- PERK protein kinase R-like ER kinase -- PKCμ protein kinase Cμ -- PNS peripheral nervous system -- RIPK1 receptor-interacting protein kinase 1 -- RT–PCR reverse transcription–polymerase chain reaction -- RyR ryanodine receptor -- SCG10 superior cervical ganglion-10 -- TNFα tumor necrosis factor α -- UPR unfolded protein response -- VGCCs voltage-gated calcium channels -- XBP1 x-box binding protein 1; endoplasmic reticulum (ER) -- ER stress -- unfolded protein response (UPR) -- axonal regeneration -- peripheral nerve injury -- growth cone; Neurochemistry -- Periodicals; Neurophysiology -- Periodicals; Neurology -- Periodicals; Neurochimie -- Périodiques; Neurophysiologie -- Périodiques; Neurochemistry; Neurophysiology; Electronic journals; Periodicals; Electronic journals; 612.8
• DOI: 10.1016/j.neuroscience.2018.02.003
• Languages: English
• ISSNs: 0306-4522

Abstract

Highlights: Ca 2+ release from ER induced by peripheral nerve injury promotes axonal UPR activation. Injury-induced axonal activation of UPR branches contributes to accelerate axonal regeneration. UPR activation in response to axonal injury regulates correct morphological changes of axonal ER and growth cones. Abstract: Adult mammalian peripheral neurons have an intrinsic regrowth capacity in response to axonal injury. The induction of calcium ion (Ca 2+ ) oscillations at an injured site is critical for the regulation of regenerative responses. In polarized neurons, distal axonal segments contain a well-developed endoplasmic reticulum (ER) network that is responsible for Ca 2+ homeostasis. Although these characteristics implicate the relevance among injury-induced Ca 2+ dynamics, axonal ER-derived signaling, and regenerative responses propagated along the axons, the details are not fully understood. In the present study, we found that Ca 2+ release from the axonal ER was accelerated in response to injury. Additionally, axonal injury-dependent Ca 2+ release from the ER activated unfolded protein response (UPR) signaling at injured sites. Inhibition of axonal UPR signaling led to fragmentation of the axonal ER and disrupted growth cone formation, suggesting that activation of axonal UPR branches following axonal injury promotes regeneration via regulation of ER reconstruction and formation of growth cones. Our studies revealed that local activation of axonal UPR signaling by injury-induced Ca 2+ release from the ER is critical for regeneration. These findings provide a new concept for the link between injury-induced signaling at a distant location and regulation of organelle and cytoskeletal formation in the orchestration of axonal regeneration.