DOCSLIB.ORG

Alpha-Synuclein Is Involved in Manganese-Induced Spatial

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Alpha-Synuclein Is Involved in Manganese-Induced Spatial Ma et al. Cell Death and Disease (2020) 11:834 https://doi.org/10.1038/s41419-020-03051-2 Cell Death & Disease ARTICLE Open Access Alpha-synuclein is involved in manganese-induced spatial memory and synaptic plasticity impairments via TrkB/Akt/Fyn-mediated phosphorylation of NMDA receptors Zhuo Ma1,KuanLiu1,Xin-RuLi1,CanWang1, Chang Liu1, Dong-Ying Yan1,YuDeng1,WeiLiu1 and Bin Xu 1 Abstract Manganese (Mn) overexposure produces long-term cognitive deficits and reduces brain-derived neurotrophic factor (BDNF) in the hippocampus. However, it remains elusive whether Mn-dependent enhanced alpha-synuclein (α-Syn) expression, suggesting a multifaceted mode of neuronal toxicities, accounts for interference with BDNF/TrkB signaling. In this study, we used C57BL/6J WT and α-Syn knockout (KO) mice to establish a model of manganism and found that Mn-induced impairments in spatial memory and synaptic plasticity were related to the α-Syn protein. In addition, consistent with the long-term potentiation (LTP) impairments that were observed, α-Syn KO relieved Mn-induced degradation of PSD95, phosphorylated CaMKIIα, and downregulated SynGAP protein levels. We transfected HT22 cells with lentivirus (LV)-α-Syn shRNA, followed by BDNF and Mn stimulation. In vitro experiments indicated that α-Syn selectively interacted with TrkB receptors and inhibited BDNF/TrkB signaling, leading to phosphorylation and downregulation of GluN2B. The binding of α-Syn to TrkB and Fyn-mediated phosphorylation of GluN2B were fi α 1234567890():,; 1234567890():,; 1234567890():,; 1234567890():,; negatively regulated by BDNF. Together, these ndings indicate that Mn-dependent enhanced -Syn expression contributes to further exacerbate BDNF protein-level reduction and to inhibit TrkB/Akt/Fyn signaling, thereby disturbing Fyn-mediated phosphorylation of the NMDA receptor GluN2B subunit at tyrosine. In KO α-Syn mice treated with Mn, spatial memory and LTP impairments were less pronounced than in WT mice. However, the same robust neuronal death was observed as a result of Mn-induced neurotoxicity. Introduction rigidity, bradykinesia, emotional instability, and intellec- Manganese (Mn) is an essential nutrient because it is tual and memory impairment at an early stage. Environ- required for cellular function in many metabolic path- mental and occupational Mn exposure occurs mainly by ways. However, the central nervous system (CNS) is welding, mining, smelters, lacquers, dry cell batteries, and highly vulnerable to Mn toxicity, which leads to many Mn-rich agrochemicals2. Bailey3 reported that Mn over- sensory disturbances and neurobehavioral deficiency. Mn exposure during development produces long-term cog- toxicity can also manifest as a disease called manganism, nitive deficits and reduces brain-derived neurotrophic which shares symptoms that are similar to those of Par- factor (BDNF) in the hippocampus. Although the neuro- kinson’s disease (PD)1. Manganism is characterized by toxic mechanisms of Mn such as oxidative stress, energy failure, and the disturbance of neurotransmitter metabo- lism are well-elucidated4, the mechanism underlying these Correspondence: Bin Xu ([email protected]) spatial learning and memory deficits is unclear. 1 Department of Environmental Health, School of Public Health, China Medical BDNF, acting through the receptor tropomyosin kinase University, No. 77 Puhe Road, Shenyang North New Area, 110122 Shenyang, Liaoning Province, People’s Republic of China receptor B (TrkB), is considered a key molecule in the Edited by A. Verkhratsky © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a linktotheCreativeCommons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. Official journal of the Cell Death Differentiation Association Ma et al. Cell Death and Disease (2020) 11:834 Page 2 of 15 neurobiological mechanisms involved in learning and from Cell Signaling Technology. TrkB, AKT, and AKT- memory5. BDNF binding to TrkB triggers its dimerization phospho-S473 primary antibodies were purchased from through conformational changes and autopho- Proteintech Biotech Co. Ltd. (China). BDNF and sphorylation of tyrosine residues in its intracellular phospho-Fyn (Y530) were purchased from Abcam Ltd. domain (ICD), activating mitogen-activated protein (Hong Kong). Secondary antibodies including horseradish kinase (MAPK), phosphatidylinositol 3-kinase (PI3K), and peroxidase (HRP)-conjugated anti-rabbit and HRP- phospholipase C-g1 (PLC-γ1) signaling pathways, and conjugated anti-mouse were purchased from Abcam mediating neural differentiation, survival, and neurogen- Ltd. (Hong Kong). esis6. However, Kang7 found that α-synuclein (α-Syn), when overexpressed, selectively interacts with TrkB Animals and treatments receptors and inhibits BDNF/TrkB signaling, leading to Homozygous α-Syn gene knockout (KO) male mice dopaminergic neuronal death. α-Syn localizes to pre- were crossed with wild-type (WT) female mice (C57BL/ synaptic terminals nearby synaptic vesicles and is pre- 6J) (Liaoning Changsheng Biotechnology Co., Ltd. SCXK dominantly expressed in the neurons of the CNS. Our 2015–0003; Benxi City, China) maintained in a stable previous research found that Mn-dependent enhanced α- breeding colony8. Syn expression leads to neuronal injury8. In addition, Mn Ten-week-old homozygous WT and α-Syn KO mice exposure promotes α-Syn secretion in exosomal vesicles. (25 ± 5 g) from an identical offspring generation of F7 The overexpression of α-Syn can disrupt synaptic func- heterozygotes were used in the in vivo experiments. The tion, resulting in cognitive disturbance9. Therefore, we WT and α-Syn KO mice were consolidated and then speculate that the overexpression of α-Syn and its sub- randomly divided into four groups (n = 10 per group) sequent interference with BDNF/TrkB signaling may play (female: male = 1:1): WT control, KO control, WT Mn an important role in linking the complicated neurobeha- treatment (100 μmol/kg MnCl2), and KO Mn treatment vioral deficiency observed following Mn exposure, (100 μmol/kg MnCl2). The control group mice were although the molecular mechanism of this process intraperitoneally (i.p.) injected with normal saline. MnCl2- remains elusive. treated mice were i.p. injected with 100 μmol/kg In this study, we provided evidence that Mn-induced MnCl2·4H2O in normal saline five times per week con- spatial learning and memory deficits are related to α-Syn secutively for 6 weeks. Animals were housed in conven- disturbing the BDNF/TrkB neurotrophic signaling path- tional enclosures at 24 ± 1 °C under a 12 h light/dark ways in vivo and in vitro. Additionally, we used shRNA to cycle. Six mice per group were chosen as the minimal knockdown α-Syn and found that BDNF/TrkB signaling number of animals needed for carrying out a comparative pathways exhibited a certain recovery. Hence, this inno- study. Blinding was performed in the experimental pro- vative finding provides insight into a pathological role(s) cedures and the data analysis. of α-Syn in mediating BDNF/TrkB signal transduction and may represent a relatively unknown mechanism by Morris water maze (MWM) test which Mn-dependent enhanced α-Syn expression is The MWM test was performed to estimate the capacity responsible for learning and memory impairments of spatial learning and memory, as previously described11. in mice. The test was composed of a circular tank (120 cm in diameter, 50 cm in height) filled with 24 °C water colored Materials and methods with white powder, and an escape platform placed 1.5 cm Chemicals below the water surface. Some geometric images were Manganese (II) chloride tetrahydrate, BDNF, and Duo- fixed around the tank to assist the swimming mice with Link proximity ligation assay (PLA) reagent were pur- their orientation, and a video camera monitored the tra- chased from Sigma Chemical Co. (St. Louis, MO, USA). jectory and transmitted the data to a computer. The mice The pGCSIL-GFP-α-Syn small hairpin RNA (shRNA)10 were placed into the pool from any quadrant, and they was purchased from Shanghai GeneChem Co. Ltd. were able to swim freely until they reached the platform. (Shanghai, China). A Cell Counting Kit-8 (CCK-8) assay This was repeated four times per day, and after 6 days of kit and lactate dehydrogenase (LDH) kit were purchased training, latency, mean speed, and mean distance were from Beyotime Biotech Co. Ltd. (China). α-Syn primary analyzed in a probe test phase, and speed, crossing times, antibody was obtained from Thermo Fisher Scientific. and time in the target quadrant were acquired after 48 h. PSD95, SynGAP, β-actin, phospho-CaMKII (Thr286), CaMKII-α, NMDA receptor 2A (GluN2A), NMDA Electrophysiology receptor 2B (GluN2B), Fyn, phospho-NMDA receptor 2A The mouse brains were carefully placed in the chilled (GluN2A) (Tyr1246), and phospho-NMDA receptor 2B artificial
Load more

Recommended publications
  • Supplemental Material
    Supplemental Table B ARGs in alphabetical order Symbol Title 3 months 6 months 9 months 12 months 23 months ANOVA Direction Category 38597 septin 2 1557 ± 44 1555 ± 44 1579 ± 56 1655 ± 26 1691 ± 31 0.05219 up Intermediate 0610031j06rik kidney predominant protein NCU-G1 491 ± 6 504 ± 14 503 ± 11 527 ± 13 534 ± 12 0.04747 up Early Adult 1G5 vesicle-associated calmodulin-binding protein 662 ± 23 675 ± 17 629 ± 16 617 ± 20 583 ± 26 0.03129 down Intermediate A2m alpha-2-macroglobulin 262 ± 7 272 ± 8 244 ± 6 290 ± 7 353 ± 16 0.00000 up Midlife Aadat aminoadipate aminotransferase (synonym Kat2) 180 ± 5 201 ± 12 223 ± 7 244 ± 14 275 ± 7 0.00000 up Early Adult Abca2 ATP-binding cassette, sub-family A (ABC1), member 2 958 ± 28 1052 ± 58 1086 ± 36 1071 ± 44 1141 ± 41 0.05371 up Early Adult Abcb1a ATP-binding cassette, sub-family B (MDR/TAP), member 1A 136 ± 8 147 ± 6 147 ± 13 155 ± 9 185 ± 13 0.01272 up Midlife Acadl acetyl-Coenzyme A dehydrogenase, long-chain 423 ± 7 456 ± 11 478 ± 14 486 ± 13 512 ± 11 0.00003 up Early Adult Acadvl acyl-Coenzyme A dehydrogenase, very long chain 426 ± 14 414 ± 10 404 ± 13 411 ± 15 461 ± 10 0.01017 up Late Accn1 amiloride-sensitive cation channel 1, neuronal (degenerin) 242 ± 10 250 ± 9 237 ± 11 247 ± 14 212 ± 8 0.04972 down Late Actb actin, beta 12965 ± 310 13382 ± 170 13145 ± 273 13739 ± 303 14187 ± 269 0.01195 up Midlife Acvrinp1 activin receptor interacting protein 1 304 ± 18 285 ± 21 274 ± 13 297 ± 21 341 ± 14 0.03610 up Late Adk adenosine kinase 1828 ± 43 1920 ± 38 1922 ± 22 2048 ± 30 1949 ± 44 0.00797 up Early
    [Show full text]
  • Neuroprotective Effects of Geniposide from Alzheimer's Disease Pathology
    Neuroprotective effects of geniposide from Alzheimer’s disease pathology WeiZhen Liu1, Guanglai Li2, Christian Hölscher2,3, Lin Li1 1. Key Laboratory of Cellular Physiology, Shanxi Medical University, Taiyuan, PR China 2. Second hospital, Shanxi medical University, Taiyuan, PR China 3. Neuroscience research group, Faculty of Health and Medicine, Lancaster University, Lancaster LA1 4YQ, UK running title: Neuroprotective effects of geniposide corresponding author: Prof. Lin Li Key Laboratory of Cellular Physiology, Shanxi Medical University, Taiyuan, PR China Email: [email protected] Neuroprotective effects of geniposide Abstract A growing body of evidence have linked two of the most common aged-related diseases, type 2 diabetes mellitus (T2DM) and Alzheimer disease (AD). It has led to the notion that drugs developed for the treatment of T2DM may be beneficial in modifying the pathophysiology of AD. As a receptor agonist of glucagon- like peptide (GLP-1R) which is a newer drug class to treat T2DM, Geniposide shows clear effects in inhibiting pathological processes underlying AD, such as and promoting neurite outgrowth. In the present article, we review possible molecular mechanisms of geniposide to protect the brain from pathologic damages underlying AD: reducing amyloid plaques, inhibiting tau phosphorylation, preventing memory impairment and loss of synapses, reducing oxidative stress and the chronic inflammatory response, and promoting neurite outgrowth via the GLP-1R signaling pathway. In summary, the Chinese herb geniposide shows great promise as a novel treatment for AD. Key words: Alzheimer’s disease, geniposide, amyloid-β, neurofibrillary tangles, oxidative stress, inflammatation, type 2 diabetes mellitus, glucagon like peptide receptor, neuroprotection, tau protein Neuroprotective effects of geniposide 1.
    [Show full text]
  • Tropomyosin Receptor Antagonism in Cylindromatosis (TRAC), an Early Phase Trial of a Topical Tropomyosin Kinase Inhibitor As
    Cranston et al. Trials (2017) 18:111 DOI 10.1186/s13063-017-1812-z STUDY PROTOCOL Open Access Tropomyosin Receptor Antagonism in Cylindromatosis (TRAC), an early phase trial of a topical tropomyosin kinase inhibitor as a treatment for inherited CYLD defective skin tumours: study protocol for a randomised controlled trial Amy Cranston1* , Deborah D. Stocken1,2, Elaine Stamp2, David Roblin3, Julia Hamlin4, James Langtry5, Ruth Plummer6, Alan Ashworth7, John Burn8 and Neil Rajan5,8 Abstract Background: Patients with germline mutations in a tumour suppressor gene called CYLD develop multiple, disfiguring, hair follicle tumours on the head and neck. The prognosis is poor, with up to one in four mutation carriers requiring complete surgical removal of the scalp. There are no effective medical alternatives to treat this condition. Whole genome molecular profiling experiments led to the discovery of an attractive molecular target in these skin tumour cells, named tropomyosin receptor kinase (TRK), upon which these cells demonstrate an oncogenic dependency in preclinical studies. Recently, the development of an ointment containing a TRK inhibitor (pegcantratinib — previously CT327 — from Creabilis SA) allowed for the assessment of TRK inhibition in tumours from patients with inherited CYLD mutations. Methods/design: Tropomysin Receptor Antagonism in Cylindromatosis (TRAC) is a two-part, exploratory, early phase, single-centre trial. Cohort 1 is a phase 1b open-labelled trial, and cohort 2 is a phase 2a randomised double-blinded exploratory placebo-controlled trial. Cohort 1 will determine the safety and acceptability of applying pegcantratinib for 4 weeks to a single tumour on a CYLD mutation carrier that is scheduled for a routine lesion excision (n = 8 patients).
    [Show full text]
  • Horizon Scanning Status Report June 2019
    Statement of Funding and Purpose This report incorporates data collected during implementation of the Patient-Centered Outcomes Research Institute (PCORI) Health Care Horizon Scanning System, operated by ECRI Institute under contract to PCORI, Washington, DC (Contract No. MSA-HORIZSCAN-ECRI-ENG- 2018.7.12). The findings and conclusions in this document are those of the authors, who are responsible for its content. No statement in this report should be construed as an official position of PCORI. An intervention that potentially meets inclusion criteria might not appear in this report simply because the horizon scanning system has not yet detected it or it does not yet meet inclusion criteria outlined in the PCORI Health Care Horizon Scanning System: Horizon Scanning Protocol and Operations Manual. Inclusion or absence of interventions in the horizon scanning reports will change over time as new information is collected; therefore, inclusion or absence should not be construed as either an endorsement or rejection of specific interventions. A representative from PCORI served as a contracting officer’s technical representative and provided input during the implementation of the horizon scanning system. PCORI does not directly participate in horizon scanning or assessing leads or topics and did not provide opinions regarding potential impact of interventions. Financial Disclosure Statement None of the individuals compiling this information have any affiliations or financial involvement that conflicts with the material presented in this report. Public Domain Notice This document is in the public domain and may be used and reprinted without special permission. Citation of the source is appreciated. All statements, findings, and conclusions in this publication are solely those of the authors and do not necessarily represent the views of the Patient-Centered Outcomes Research Institute (PCORI) or its Board of Governors.
    [Show full text]
  • (12) Patent Application Publication (10) Pub. No.: US 2010/0317005 A1 Hardin Et Al
    US 20100317005A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2010/0317005 A1 Hardin et al. (43) Pub. Date: Dec. 16, 2010 (54) MODIFIED NUCLEOTIDES AND METHODS (22) Filed: Mar. 15, 2010 FOR MAKING AND USE SAME Related U.S. Application Data (63) Continuation of application No. 11/007,794, filed on Dec. 8, 2004, now abandoned, which is a continuation (75) Inventors: Susan H. Hardin, College Station, in-part of application No. 09/901,782, filed on Jul. 9, TX (US); Hongyi Wang, Pearland, 2001. TX (US); Brent A. Mulder, (60) Provisional application No. 60/527,909, filed on Dec. Sugarland, TX (US); Nathan K. 8, 2003, provisional application No. 60/216,594, filed Agnew, Richmond, TX (US); on Jul. 7, 2000. Tommie L. Lincecum, JR., Publication Classification Houston, TX (US) (51) Int. Cl. CI2O I/68 (2006.01) Correspondence Address: (52) U.S. Cl. ............................................................ 435/6 LIFE TECHNOLOGES CORPORATION (57) ABSTRACT CFO INTELLEVATE Labeled nucleotide triphosphates are disclosed having a label P.O. BOX S2OSO bonded to the gamma phosphate of the nucleotide triphos MINNEAPOLIS, MN 55402 (US) phate. Methods for using the gamma phosphate labeled nucleotide are also disclosed where the gamma phosphate labeled nucleotide are used to attach the labeled gamma phos (73) Assignees: LIFE TECHNOLOGIES phate in a catalyzed (enzyme or man-made catalyst) reaction to a target biomolecule or to exchange a phosphate on a target CORPORATION, Carlsbad, CA biomolecule with a labeled gamme phosphate. Preferred tar (US); VISIGEN get biomolecules are DNAs, RNAs, DNA/RNAs, PNA, BIOTECHNOLOGIES, INC. polypeptide (e.g., proteins enzymes, protein, assemblages, etc.), Sugars and polysaccharides or mixed biomolecules hav ing two or more of DNAs, RNAs, DNA/RNAs, polypeptide, (21) Appl.
    [Show full text]
  • Regression of Epileptogenesis by Inhibiting Trkb Signaling Following A
    RESEARCH ARTICLE Regression of Epileptogenesis by Inhibiting Tropomyosin Kinase B Signaling following a Seizure Kamesh Krishnamurthy, MD, PhD ,1 Yang Zhong Huang, PhD,1 Stephen C. Harward, MD, PhD,2 Keshov K. Sharma, BS,1 Dylan L. Tamayo,1 and James O. McNamara, MD1,3,4 Objective: Temporal lobe epilepsy (TLE) is a devastating disease in which seizures persist in 35% of patients despite optimal use of antiseizure drugs. Clinical and preclinical evidence implicates seizures themselves as one factor promot- ing epilepsy progression. What is the molecular consequence of a seizure that promotes progression? Evidence from preclinical studies led us to hypothesize that activation of tropomyosin kinase B (TrkB)–phospholipase-C-gamma-1 (PLCγ1) signaling induced by a seizure promotes epileptogenesis. Methods: To examine the effects of inhibiting TrkB signaling on epileptogenesis following an isolated seizure, we implemented a modified kindling model in which we induced a seizure through amygdala stimulation and then used either a chemical–genetic strategy or pharmacologic methods to disrupt signaling for 2 days following the seizure. The severity of a subsequent seizure was assessed by behavioral and electrographic measures. Results: Transient inhibition of TrkB-PLCγ1 signaling initiated after an isolated seizure limited progression of epi- leptogenesis, evidenced by the reduced severity and duration of subsequent seizures. Unexpectedly, transient inhibi- tion of TrkB-PLCγ1 signaling initiated following a seizure also reverted a subset of animals to an earlier state of epileptogenesis. Remarkably, inhibition of TrkB-PLCγ1 signaling in the absence of a recent seizure did not reduce severity of subsequent seizures. Interpretation: These results suggest a novel strategy for limiting progression or potentially ameliorating severity of TLE whereby transient inhibition of TrkB-PLCγ1 signaling is initiated following a seizure.
    [Show full text]
  • Natural Psychoplastogens As Antidepressant Agents
    molecules Review Natural Psychoplastogens As Antidepressant Agents Jakub Benko 1,2,* and Stanislava Vranková 1 1 Center of Experimental Medicine, Institute of Normal and Pathological Physiology, Slovak Academy of Sciences, 841 04 Bratislava, Slovakia; [email protected] 2 Faculty of Medicine, Comenius University, 813 72 Bratislava, Slovakia * Correspondence: [email protected]; Tel.: +421-948-437-895 Academic Editor: Olga Pecháˇnová Received: 31 December 2019; Accepted: 2 March 2020; Published: 5 March 2020 Abstract: Increasing prevalence and burden of major depressive disorder presents an unavoidable problem for psychiatry. Existing antidepressants exert their effect only after several weeks of continuous treatment. In addition, their serious side effects and ineffectiveness in one-third of patients call for urgent action. Recent advances have given rise to the concept of psychoplastogens. These compounds are capable of fast structural and functional rearrangement of neural networks by targeting mechanisms previously implicated in the development of depression. Furthermore, evidence shows that they exert a potent acute and long-term positive effects, reaching beyond the treatment of psychiatric diseases. Several of them are naturally occurring compounds, such as psilocybin, N,N-dimethyltryptamine, and 7,8-dihydroxyflavone. Their pharmacology and effects in animal and human studies were discussed in this article. Keywords: depression; antidepressants; psychoplastogens; psychedelics; flavonoids 1. Introduction 1.1. Depression Depression is the most common and debilitating mental disease. Its prevalence and burden have been steadily rising in the past decades. For example, in 1990, the World Health Organization (WHO) projected that depression would increase from 4th to 2nd most frequent cause of world-wide disability by 2020 [1].
    [Show full text]
  • Horizon Scanning Status Report, Volume 2
    PCORI Health Care Horizon Scanning System Volume 2, Issue 3 Horizon Scanning Status Report September 2020 Prepared for: Patient-Centered Outcomes Research Institute 1828 L St., NW, Suite 900 Washington, DC 20036 Contract No. MSA-HORIZSCAN-ECRI-ENG-2018.7.12 Prepared by: ECRI Institute 5200 Butler Pike Plymouth Meeting, PA 19462 Investigators: Randy Hulshizer, MA, MS Damian Carlson, MS Christian Cuevas, PhD Andrea Druga, PA-C Marcus Lynch, PhD, MBA Misha Mehta, MS Prital Patel, MPH Brian Wilkinson, MA Donna Beales, MLIS Jennifer De Lurio, MS Eloise DeHaan, BS Eileen Erinoff, MSLIS Cassia Hulshizer, AS Madison Kimball, MS Maria Middleton, MPH Diane Robertson, BA Melinda Rossi, BA Kelley Tipton, MPH Rosemary Walker, MLIS Andrew Furman, MD, MMM, FACEP Statement of Funding and Purpose This report incorporates data collected during implementation of the Patient-Centered Outcomes Research Institute (PCORI) Health Care Horizon Scanning System, operated by ECRI under contract to PCORI, Washington, DC (Contract No. MSA-HORIZSCAN-ECRI-ENG-2018.7.12). The findings and conclusions in this document are those of the authors, who are responsible for its content. No statement in this report should be construed as an official position of PCORI. An intervention that potentially meets inclusion criteria might not appear in this report simply because the Horizon Scanning System has not yet detected it or it does not yet meet inclusion criteria outlined in the PCORI Health Care Horizon Scanning System: Horizon Scanning Protocol and Operations Manual. Inclusion or absence of interventions in the horizon scanning reports will change over time as new information is collected; therefore, inclusion or absence should not be construed as either an endorsement or rejection of specific interventions.
    [Show full text]
  • Neuron-Satellite Glial Cell Interactions in Sympathetic Nervous System Development
    NEURON-SATELLITE GLIAL CELL INTERACTIONS IN SYMPATHETIC NERVOUS SYSTEM DEVELOPMENT by Erica D. Boehm A dissertation submitted to the Johns Hopkins University in conformity with the requirements for the degree of Doctor of Philosophy Baltimore, Maryland July 2020 © 2020 Erica Boehm All rights reserved. ABSTRACT Glial cells play crucial roles in maintaining the stability and structure of the nervous system. Satellite glial cells are a loosely defined population of glial cells that ensheathe neuronal cell bodies, dendrites, and synapses of the peripheral nervous system (Elfvin and Forsman 1978; Pannese 1981). Satellite glial cells are closely juxtaposed to peripheral neurons with only 20nm of space between their membranes (Dixon 1969). This close association suggests a tight coupling between the cells to allow for possible exchange of important nutrients, yet very little is known about satellite glial cell function and development. How neurons and glial cells co-develop to create this tightly knit unit remains undefined, as well as the functional consequences of disrupting these contacts. Satellite glial cells are derived from the same population of cells that give rise to peripheral neurons, but do not begin differentiation and proliferation until neurogenesis has been completed (Hall and Landis 1992). A key signaling pathway involved in glial specification is the Delta/Notch signaling pathway (Tsarovina et al. 2008). However, recent studies also implicate Notch signaling in the maturation of glia through non- canonical Notch ligands such as Delta/Notch-like EGF-related Receptor (DNER) (Eiraku et al. 2005). Interestingly, it has been reported that levels of DNER in sympathetic neurons may be dependent on the target-derived growth factor, nerve growth factor (NGF), and this signal is prominent in sympathetic neurons at the time in which satellite glial cells are developing (Deppmann et al.
    [Show full text]
  • Supplementary Tables
    Supplemental Data Table 1. Peptide number Sequence Kinase Barrett / Squamous 183 SSLKSRKRA 2.46 152 KRPSKRAKA PKC 2.39 164 SSKRAK PKC 2.25 995 RQRKSRRTI PKC 2.11 926 KYRKSSLKS 2.07 195 LRGRSFMNN PKA 1.85 389 SRTASFSES PKB 1.77 650 EDTLSDSDD CKII 1.75 23 SPRKSPKKS sperm-specific histone kinase 1.73 179 RKQISVRGL PK 1.73 239 KASASPRRK sperm-specific 1.67 369 SLRASTSKS S6K 1.66 368 RSGYSSPGS 1.66 34 RKRSAKE PKA,PKG 1.65 1062 SPRKSPRKS sperm-specific 1.65 900 AAASFKAKR PKC 1.61 201 HMRSSMSGL PKA 1.55 316 RGKSSSYSK PKC 1.52 566 RRATPA 1.51 1096 AAASFKAKK PKC 1.51 45 KRAKAKTAKKR PKC 1.50 941 DPTMSKKKK PKC 1.49 352 DAGASPVEK PKC 1.49 380 PLTPSGEAP Src 1.49 356 EGTHSTKRG PKC 1.48 351 GSRGSGSSV PKA 1.47 30 TLASSFKRR PKC 1.46 793 ALGISYGRK PKC 1.46 833 LTRRASFSAQ PKA 1.45 807 SPKKSPRKA sperm-specific 1.45 705 ARKKSSAQL PKA 1.44 364 GEINTEDDD CKII 1.44 231 VIKRSPRKR CDK 1.43 180 AGTTYAL MHCK 1.43 348 KRPSIRAKA PKC 1.43 169 RLSPSPTSQ CDK 1.42 969 LGSALRRR 1.40 166 AVDRYIAIT IR 1.39 1044 RRLSSLRAS S6K 1.38 244 KRSGSVYEP PKA 1.37 1110 REILSRRPS GSK3 1.36 574 YKNDYYRKR 1.36 167 DPLLTYRFP PKC 1.36 1033 EQEEYEDPD Lyn,Syk 1.35 189 VKRGISGL H4-PK-I,PKA 1.35 154 PYKFPSSPLRIPGZ na 1.33 349 NPGFYVEAN EGFR 1.32 1149 RKRKSSQAL PKA 1.31 827 KAKTTKKRP 1.31 151 ESSNYMAPY PDGFR 1.30 551 GTVPSDNID GRK2,GRK5 1.30 337 KLRRSSSVG PKA,PKC 1.29 571 RKFSSARPE PKA 1.28 362 AVDGYVKPQ Lyn,Src,JAK2 1.28 188 PQPEYVNQP erbB2 1.27 786 KRPSNRAKA PKC 1.25 158 GGRDSRSGS PKA,PKC 1.25 1063 RRRASVA PKA,PKC 1.25 156 DAHKSKRQH CKII 1.24 915 GRGLSLSR PKA 1.20 49 KRKQGSVRGL PhK,PKA 1.16
    [Show full text]
  • 蛋白激酶与神经系统功能调控 曹 帅1，王 韵1,2* (1 北京大学基础医学院神经生物学系，北京大学神经科学研究所，教育部/卫生计生委 重点实验室，北京 100191；2 北京大学麦戈文脑研究所，北京 100871)
    第27卷 第3期 生命科学 Vol. 27, No. 3 2015年3月 Chinese Bulletin of Life Sciences Mar., 2015 DOI: 10.13376/j.cbls/2015041 文章编号：1004-0374(2015)03-0306-10 王韵，北京大学基础医学院副院长，神经科学研究所副所长，神经生物 学系副主任、教授、博士生导师，北京大学麦戈文脑科学研究所课题组长，国 家杰出青年基金获得者，教育部长江特聘教授。兼任中国生理学会副理事长 及秘书长，国际神经肽协会中国分会秘书长，中国神经科学学会理事，教育 部基础医学指导委员会及中华医学会基础医学分会秘书长，北京神经科学学 会副理事长。系列文章发表在神经科学国际专业杂志上，获国家发明专利 3 项。 曾获教育部高校优秀青年教师称号及奖励基金、全国优秀科学科技工作者、张 香桐神经科学青年科学家奖、北京市“教育先锋”先进个人及北京市高等教 育教学名师等荣誉称号。课题组研究方向是神经系统细胞信号转导通路的研 究，重点集中两个方面。一是痛与痛觉调制的细胞信号转导通路 ：旨在病理 性疼痛模型上，研究外周和中枢神经元发生的可塑性变化及其与痛感受与痛 情绪的关系，并围绕细胞信号转导的核心分子——蛋白激酶，深入探讨慢性痛 产生相关的信号通路，以期发现新的镇痛靶点或镇痛药物，为解决临床镇痛 问题提供新思路。另一个是神经发育和损伤修复机制 ：旨在探讨参与神经元 极性建立、迁移、树突发育、突触形成和修剪等神经发育过程，以及外周神 经损伤后修复 ( 与发育过程享有一些共同的分子机制 ) 和神经元缺血损伤 / 抗 损伤过程的关键分子，旨在阐明先天性神经发育疾病和后天性神经损伤如机 械、缺血损伤等过程的病理机制，找到其中的关键分子，设计可能的干预策略， 从而为一些临床常见神经精神疾病的治疗提出新方法。 蛋白激酶与神经系统功能调控 曹 帅1，王 韵1,2* (1 北京大学基础医学院神经生物学系，北京大学神经科学研究所，教育部/卫生计生委 重点实验室，北京 100191；2 北京大学麦戈文脑研究所，北京 100871) 摘 要 ：翻译后的磷酸化修饰是蛋白质结构和功能的重要调节方式。催化蛋白质磷酸化过程的蛋白激酶广 泛参与神经发育、感觉、学习记忆、情绪与认知等生理过程及神经退行性疾病、慢性疼痛及精神疾病等病 理生理过程，是生命科学领域的研究热点。现将举例说明蛋白激酶在神经系统内的重要作用，并介绍以蛋 白激酶为靶点的药物开发现况。 关键词 ：神经系统 ；蛋白激酶；Cdk5 ；PKD1 ；LIMK 中图分类号 ： Q42 ； Q555 文献标志码 ：A Protein kinases and the functional regulation in the nervous system: a review of illustration with examples CAO Shuai1, WANG Yun1,2* 收稿日期：2015-01-17 基金项目：国家自然科学基金杰出青年基金项目(30925015)；国家自然科学基金重点项目(30830044)；国家自然科学中 加合作基金项目(91332119)；国家重点基础研究发展计划(“973”项目)(2014CB542204) *通信作者：E-mail: [email protected] 第3期 曹 帅，等：蛋白激酶与神经系统功能调控 307 (1 Key Laboratory for Neuroscience of Ministry of Education and Health, Neuroscience Research Institute and Department of Neurobiology, Peking University, Beijing 100191, China; 2 PKU-IDG/McGovern Institute for Brain Research, Peking University, Beijing 100871, China) Abstract: Post-translational phosphorylation modification plays vital roles in modulating protein structure and function. Protein kinases, which catalyze the phosphorylation reaction of substrate protein, take part in most physiological neural processes such as sensory perception, learning and memory, emotion and cognition.
    [Show full text]
  • 12) United States Patent (10
    US007635572B2 (12) UnitedO States Patent (10) Patent No.: US 7,635,572 B2 Zhou et al. (45) Date of Patent: Dec. 22, 2009 (54) METHODS FOR CONDUCTING ASSAYS FOR 5,506,121 A 4/1996 Skerra et al. ENZYME ACTIVITY ON PROTEIN 5,510,270 A 4/1996 Fodor et al. MICROARRAYS 5,512,492 A 4/1996 Herron et al. 5,516,635 A 5/1996 Ekins et al. (75) Inventors: Fang X. Zhou, New Haven, CT (US); 5,532,128 A 7/1996 Eggers Barry Schweitzer, Cheshire, CT (US) 5,538,897 A 7/1996 Yates, III et al. s s 5,541,070 A 7/1996 Kauvar (73) Assignee: Life Technologies Corporation, .. S.E. al Carlsbad, CA (US) 5,585,069 A 12/1996 Zanzucchi et al. 5,585,639 A 12/1996 Dorsel et al. (*) Notice: Subject to any disclaimer, the term of this 5,593,838 A 1/1997 Zanzucchi et al. patent is extended or adjusted under 35 5,605,662 A 2f1997 Heller et al. U.S.C. 154(b) by 0 days. 5,620,850 A 4/1997 Bamdad et al. 5,624,711 A 4/1997 Sundberg et al. (21) Appl. No.: 10/865,431 5,627,369 A 5/1997 Vestal et al. 5,629,213 A 5/1997 Kornguth et al. (22) Filed: Jun. 9, 2004 (Continued) (65) Prior Publication Data FOREIGN PATENT DOCUMENTS US 2005/O118665 A1 Jun. 2, 2005 EP 596421 10, 1993 EP 0619321 12/1994 (51) Int. Cl. EP O664452 7, 1995 CI2O 1/50 (2006.01) EP O818467 1, 1998 (52) U.S.
    [Show full text]