Unfolded protein response (UPR) has roles not only in resolving the accumulation of unfolded proteins owing to endoplasmic reticulum (ER) stress, but also in regulation of cellular physiological functions. ER stress transducers providing the branches of UPR signaling are known to localize in distal dendritic ER of neurons. These reports suggest that local activation of UPR branches may produce integrated outputs for distant communication, and allow regulation of local events in highly polarized neurons. Here, we demonstrated that synaptic activity-and brain-derived neurotrophic factor (BDNF)-dependent local activation of UPR signaling could be associated with dendritic functions through retrograde signal propagation by using murine neuroblastoma cell line, Neuro-2A and primary cultured hippocampal neurons derived from postnatal day 0 litter C57BL/6 mice. ER stress transducer, inositol-requiring kinase 1 (IRE1), was activated at postsynapses in response to excitatory synaptic activation.Activated dendritic IRE1 accelerated accumulation of the downstream transcription factor, x-box-binding protein 1 (XBP1), in the nucleus. Interestingly, excitatory synaptic activation-dependent up-regulation of XBP1 directly facilitated transcriptional activation of BDNF. BDNF in turn drove its own expression via IRE1-XBP1 pathway in a protein kinase A-dependent manner. Exogenous treatment with BDNF promoted extension and branching of dendrites through the protein kinase A-IRE1-XBP1 cascade. Taken together, our findings indicate novel mechanisms for communication between soma and distal sites of polarized neurons that are coordinated by local activation of IRE1-XBP1 signaling. Synaptic activity-and BDNF-dependent distinct activation of dendritic IRE1-XBP1 cascade drives BDNF expression in cell soma and may be involved in dendritic extension. Keywords: BDNF, dendrite, endoplasmic reticulum stress, IRE1, unfolded protein response, XBP1. Abbreviations used: ATF6, activating transcription factor 6; BDNF, brain-derived neurotrophic factor; BiP, binding immunoglobulin protein; bp, base pair; cAMP, cyclic adenosine monophosphate; ChIP, chromatin immunoprecipitation; CNS, central nervous system; CREB, cAMP response element-binding protein; eIF2a, a subunit of eukaryotic initiation factor 2; ERAD, ER-associated degradation; ER, endoplasmic reticulum; GFP, green fluorescence protein; GluR, glutamate receptor; IRE1, inositol requiring 1; LTP, long-term potentiation; MAP2, microtubule-associated protein 2; p38 MAPK, p38 mitogen activated protein kinase; PERK, protein kinase R-like ER kinase; PKA, protein kinase A; PSD95, postsynaptic density protein 95; ROCKII, Rhoassociated protein kinase II; S6K1, ribosomal protein S6 kinase 1; TrkB, tropomyosin-related kinase B; UPRE, unfolded protein response element; UPR, unfolded protein response; XBP1, x-box-binding protein 1.

This is an open access article under the terms of the Creat ive Commo ns Attri butio n-NonCo mmercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. AbstractIntramembrane cleavage of transmembrane proteins is a fundamental cellular process to produce important signals that elicit biological responses. These proteolytic events are known as regulated intramembrane proteolysis (RIP). ATF6 and BBF2H7 are transmembrane basic leucine zipper transcription factors and are subjected to RIP by site-1 protease (S1P) and site-2 protease (S2P) sequentially in response to endoplasmic reticulum (ER) stress. However, the detailed mechanisms responsible for RIP of the transcription factors, including the precise cutting sites, are still unknown. In this study, we demonstrated that S1P cleaves BBF2H7 just before the RXXL S1P recognition motif. Conversely, S2P cut at least three different sites in the membrane (next to Leu380, Met381, and Leu385), indicating that S2P cleaves the substrates at variable sites or via a multistep process. Interestingly, we found BBF2H7-derived small peptide (BSP) fragments located between the S1P and S2P cleavage sites in cells exposed to ER stress. Major type of BSP fragments was composed of 45 amino acid including partial transmembrane and luminal regions and easily aggregates like amyloid β (Aβ) protein. These results advance the understanding of poorly characterized ER stress-dependent RIP. Furthermore, the aggregable peptides produced by ER stress could link to the pathophysiology of neurodegenerative disorders. |MATSUHISA eT Al.

No abstract

BackgroundThe fully endoscopic supraorbital trans-eyebrow keyhole approach is a technique utilized for the transcranial resection of tuberculum sellae meningioma (TSM). Surgery is the first choice for TSM treatment. This study aimed to summarize and analyze the safety, feasibility, limitations, and technical requirements of the fully endoscopic supraorbital trans-eyebrow keyhole approach for TSM resection.MethodsData of 19 TSM fully endoscopic supraorbital trans-eyebrow keyhole approach resections cases (six and 13 on the left and right eyebrows, respectively) were retrospectively analyzed at the Neurosurgery Department of the First Affiliated Hospital of Bengbu Medical College (Bengbu, China) from August 2015 to March 2022.ResultsAll 19 patients were diagnosed with meningioma (World Health Organization grade I), and according to the scope of tumor resection (EOR), 18 patients (94.7%) had gross total resection (GTR), and one patient (5.3%) had near-total resection (NTR). Preoperative chief complaints were symptomatic visual dysfunction (n = 12), headache and dizziness (n = 6), and accidental discovery (n = 1). Postoperative visual function improved in 83.3% of cases (10/12), and headache and dizziness were relieved in 83.3% of cases (5/6 patients). Postoperative intracranial infection occurred in one case and was cured by external drainage of the lumbar cistern and anti-infective treatment. Two cases of frontal lobe injury were discharged after conservative treatment. There was no postoperative olfactory dysfunction, eyelid ptosis, cerebrospinal fluid leakage, or death. There were no reports of disease recurrence or death during the 3-month follow-up at an outpatient clinic or by telephone.ConclusionFully endoscopic TSM resection through the keyhole approach is safe and feasible. It can be used to explore angles that cannot be seen under a microscope and show the true value of endoscopy technology. The endoscopic equipment and technical skills of the surgeon and surgical team are important in this technique.