Coupling of Terminal Differentiation Deficit with Neurodegenerative Pathology in Vps35-Deficient Pyramidal Neurons
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DF2589-MUL1 Antibody
Affinity Biosciences website:www.affbiotech.com order:[email protected] MUL1 Antibody Cat.#: DF2589 Concn.: 1mg/ml Mol.Wt.: 38 kDa Size: 50ul,100ul,200ul Source: Rabbit Clonality: Polyclonal Application: WB 1:500-1:2000, ELISA(peptide) 1:20000-1:40000 *The optimal dilutions should be determined by the end user. Reactivity: Human,Mouse,Rat Purification: The antiserum was purified by peptide affinity chromatography using SulfoLink™ Coupling Resin (Thermo Fisher Scientific). Specificity: MUL1 Antibody detects endogenous levels of total MUL1. Immunogen: A synthesized peptide derived from human MUL1, corresponding to a region within the internal amino acids. Uniprot: Q969V5 Description: Exhibits weak E3 ubiquitin-protein ligase activity, but preferentially acts as a SUMO E3 ligase at physiological concentrations. Plays a role in the control of mitochondrial morphology. Promotes mitochondrial fragmentation and influences mitochondrial localization. Inhibits cell growth. When overexpressed, activates JNK through MAP3K7/TAK1 and induces caspase-dependent apoptosis. E3 ubiquitin ligases accept ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and then directly transfer the ubiquitin to targeted substrates. Storage Condition and Rabbit IgG in phosphate buffered saline, pH 7.4, 150mM Buffer: NaCl, 0.02% sodium azide and 50% glycerol. Western blot analysis of extracts from various samples, using MUL1 Antibody. Lane 1: Rat liver, blocked with antigen-specific peptides, Lane 2: Rat liver, Lane 3: Hela cells. 1 / 2 Affinity Biosciences website:www.affbiotech.com order:[email protected] Western blot analysis of MUL1 expression in A431 whole cell lysates ,The lane on the left was treated with the antigen- specific peptide. -
MUL1 Polyclonal Antibody Catalog Number PA5-29550 Product Data Sheet
Lot Number: TE2564971L Website: thermofisher.com Customer Service (US): 1 800 955 6288 ext. 1 Technical Support (US): 1 800 955 6288 ext. 441 thermofisher.com/contactus MUL1 Polyclonal Antibody Catalog Number PA5-29550 Product Data Sheet Details Species Reactivity Size 100 µL Tested species reactivity Human Host / Isotype Rabbit IgG Tested Applications Dilution * Class Polyclonal Immunocytochemistry (ICC) 1:100-1:1000 Type Antibody Immunofluorescence (IF) 1:100-1:1000 Recombinant fragment Immunohistochemistry (Paraffin) Immunogen corresponding to a region within 1:100-1:1000 amino acids 1 and 352 of Human (IHC (P)) MUL1 Western Blot (WB) 1:500-1:3000 Conjugate Unconjugated * Suggested working dilutions are given as a guide only. It is recommended that the user titrate the product for use in their Form Liquid own experiment using appropriate negative and positive controls. Concentration 1.34mg/ml Purification Antigen affinity chromatography Storage Buffer PBS, pH 7, with 1% BSA, 20% glycerol Contains 0.025% Proclin 300 Storage Conditions -20° C, Avoid Freeze/Thaw Cycles Product Specific Information PA5-29550 targets MUL1 in IF and WB applications and shows reactivity with Human samples. The PA5-29550 immunogen is recombinant fragment corresponding to a region within amino acids 1 and 352 of Human MUL1. Background/Target Information E3 ubiquitin-protein ligase that plays a role in the control of mitochondrial morphology. Promotes mitochondrial fragmentation and influences mitochondrial localization. Inhibits cell growth. When overexpressed, activates JNK through MAP3K7/TAK1 and induces caspase-dependent apoptosis. E3 ubiquitin ligases accept ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and then directly transfer the ubiquitin to targeted substrates. -
Do Thin Spines Learn to Be Mushroom Spines That Remember? Jennifer Bourne and Kristen M Harris
CONEUR-488; NO OF PAGES 6 Do thin spines learn to be mushroom spines that remember? Jennifer Bourne and Kristen M Harris Dendritic spines are the primary site of excitatory input on most or whether they instead switch shapes depending on principal neurons. Long-lasting changes in synaptic activity are synaptic plasticity during learning. accompanied by alterations in spine shape, size and number. The responsiveness of thin spines to increases and decreases Maturation and stabilization of spines in synaptic activity has led to the suggestion that they are Spines tend to stabilize with maturation [5]; however, a ‘learning spines’, whereas the stability of mushroom spines small proportion continues to turnover in more mature suggests that they are ‘memory spines’. Synaptic brains [5–7]. The transient spines are thin spines that enhancement leads to an enlargement of thin spines into emerge and disappear over a few days, whereas mush- mushroom spines and the mobilization of subcellular resources room spines can persist for months [5,6]. Mushroom to potentiated synapses. Thin spines also concentrate spines have larger postsynaptic densities (PSDs) [1], biochemical signals such as Ca2+, providing the synaptic which anchor more AMPA glutamate receptors and make specificity required for learning. Determining the mechanisms these synapses functionally stronger [8–12]. Mushroom that regulate spine morphology is essential for understanding spines are more likely than thin spines to contain smooth the cellular changes that underlie learning and memory. endoplasmic reticulum, which can regulate Ca2+ locally [13], and spines that have larger synapses are also more Addresses Center for Learning and Memory, Department of Neurobiology, likely to contain polyribosomes for local protein synthesis University of Texas, Austin, TX 78712-0805, USA [14]. -
Efficacy and Mechanistic Evaluation of Tic10, a Novel Antitumor Agent
University of Pennsylvania ScholarlyCommons Publicly Accessible Penn Dissertations 2012 Efficacy and Mechanisticv E aluation of Tic10, A Novel Antitumor Agent Joshua Edward Allen University of Pennsylvania, [email protected] Follow this and additional works at: https://repository.upenn.edu/edissertations Part of the Oncology Commons Recommended Citation Allen, Joshua Edward, "Efficacy and Mechanisticv E aluation of Tic10, A Novel Antitumor Agent" (2012). Publicly Accessible Penn Dissertations. 488. https://repository.upenn.edu/edissertations/488 This paper is posted at ScholarlyCommons. https://repository.upenn.edu/edissertations/488 For more information, please contact [email protected]. Efficacy and Mechanisticv E aluation of Tic10, A Novel Antitumor Agent Abstract TNF-related apoptosis-inducing ligand (TRAIL; Apo2L) is an endogenous protein that selectively induces apoptosis in cancer cells and is a critical effector in the immune surveillance of cancer. Recombinant TRAIL and TRAIL-agonist antibodies are in clinical trials for the treatment of solid malignancies due to the cancer-specific cytotoxicity of TRAIL. Recombinant TRAIL has a short serum half-life and both recombinant TRAIL and TRAIL receptor agonist antibodies have a limited capacity to perfuse to tissue compartments such as the brain, limiting their efficacy in certain malignancies. To overcome such limitations, we searched for small molecules capable of inducing the TRAIL gene using a high throughput luciferase reporter gene assay. We selected TRAIL-inducing compound 10 (TIC10) for further study based on its induction of TRAIL at the cell surface and its promising therapeutic index. TIC10 is a potent, stable, and orally active antitumor agent that crosses the blood-brain barrier and transcriptionally induces TRAIL and TRAIL-mediated cell death in a p53-independent manner. -
The Contributions of Microglial Vps35 to Adult Hippocampal Neurogenesis and Neurodegenerative Disorders
THE CONTRIBUTIONS OF MICROGLIAL VPS35 TO ADULT HIPPOCAMPAL NEUROGENESIS AND NEURODEGENERATIVE DISORDERS By Joanna Ruth Erion Submitted to the Faculty of the Graduate School of Augusta University in partial fulfillment of the Requirements of the Degree of Doctor of Philosophy April 2017 COPYRIGHT© 2017 by Joanna Ruth Erion THE CONTRIBUTIONS OF MICROGLIAL VPS35 TO ADULT HIPPOCAMPAL NEUROGENESIS AND NEURODEGENERATIVE DISORDERS This thesis/dissertation is submitted by Joanna Ruth Erion and has been examined and approved by an appointed committee of the faculty of the Graduate School of Augusta University. The signatures which appear below verify the fact that all required changes have been incorporated and that the thesis/dissertation has received final approval with reference to content, form and accuracy of presentation. This thesis/dissertation is therefore in partial fulfillment of the requirements for the degree of Doctor of Philosophy). ___________________ __________________________________ Date Major Advisor __________________________________ Departmental Chairperson __________________________________ Dean, Graduate School ACKNOWLEDGEMENTS I will be forever grateful to my mentor, Dr. Wen-Cheng Xiong, for welcoming me into her laboratory and providing me with the honor and opportunity to work under her astute leadership. I have learned many valuable lessons under her guidance, all of which have enabled me to grow as both a student and a scientist. It was with her erudite guidance and suggestions that I was able to examine aspects of my investigations that I had yet to consider and ask questions that would not have otherwise occurred to me. I would also like to thank Dr. Lin Mei for contributing not only his laboratory and resources to my endeavors, but also his guidance and input into my investigations, providing me with additional avenues for directing my efforts. -
Cooperative Astrocyte and Dendritic Spine Dynamics at Hippocampal Excitatory Synapses
The Journal of Neuroscience, August 30, 2006 • 26(35):8881–8891 • 8881 Development/Plasticity/Repair Cooperative Astrocyte and Dendritic Spine Dynamics at Hippocampal Excitatory Synapses Michael Haber, Lei Zhou, and Keith K. Murai Centre for Research in Neuroscience, Department of Neurology and Neurosurgery, The Research Institute of the McGill University Health Centre, Montreal General Hospital, Montreal, Quebec, H3G 1A4, Canada Accumulating evidence is redefining the importance of neuron–glial interactions at synapses in the CNS. Astrocytes form “tripartite” complexes with presynaptic and postsynaptic structures and regulate synaptic transmission and plasticity. Despite our understanding of the importance of neuron–glial relationships in physiological contexts, little is known about the structural interplay between astrocytes and synapses. In the past, this has been difficult to explore because studies have been hampered by the lack of a system that preserves complex neuron–glial relationships observed in the brain. Here we present a system that can be used to characterize the intricate relationshipbetweenastrocyticprocessesandsynapticstructuresinsituusingorganotypichippocampalslices,apreparationthatretains the three-dimensional architecture of astrocyte–synapse interactions. Using time-lapse confocal imaging, we demonstrate that astro- cytes can rapidly extend and retract fine processes to engage and disengage from motile postsynaptic dendritic spines. Surprisingly, astrocytic motility is, on average, higher than its dendritic spine -
Protein Kinases and Parkinson's Disease
International Journal of Molecular Sciences Review Protein Kinases and Parkinson’s Disease Syed Jafar Mehdi 1, Hector Rosas-Hernandez 2, Elvis Cuevas 2, Susan M. Lantz 2, Steven W. Barger 1,3, Sumit Sarkar 2, Merle G. Paule 2, Syed F. Ali 2 and Syed Z. Imam 1,2,* 1 Department of Geriatrics, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA; [email protected] (S.J.M.); [email protected] (S.W.B.) 2 Division of Neurotoxicology, National Center for Toxicological Research/US Food and Drug Administration, Jefferson, AR 72079, USA; [email protected] (H.R.-H.); [email protected] (E.C.); [email protected] (S.M.L.); [email protected] (S.S.); [email protected] (M.G.P.); [email protected] (S.F.A.) 3 Geriatric Research Education and Clinical Center, Central Arkansas Veterans Healthcare System, Little Rock, AR 72205, USA * Correspondence: [email protected]; Tel.: +1-870-543-7989; Fax: +1-870-543-7745 Academic Editor: Katalin Prokai-Tatrai Received: 30 May 2016; Accepted: 1 September 2016; Published: 20 September 2016 Abstract: Currently, the lack of new drug candidates for the treatment of major neurological disorders such as Parkinson’s disease has intensified the search for drugs that can be repurposed or repositioned for such treatment. Typically, the search focuses on drugs that have been approved and are used clinically for other indications. Kinase inhibitors represent a family of popular molecules for the treatment and prevention of various cancers, and have emerged as strong candidates for such repurposing because numerous serine/threonine and tyrosine kinases have been implicated in the pathobiology of Parkinson’s disease. -
Parkinson's Disease Causative Mutation in Vps35 Disturbs Tetherin
cells Article Parkinson’s Disease Causative Mutation in Vps35 Disturbs Tetherin Trafficking to Cell Surfaces and Facilitates Virus Spread Yingzhuo Ding 1,†, Yan Li 1,† , Gaurav Chhetri 1 , Xiaoxin Peng 1, Jing Wu 1, Zejian Wang 1, Bo Zhao 1 , Wenjuan Zhao 1 and Xueyi Li 1,2,* 1 School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China; [email protected] (Y.D.); [email protected] (Y.L.); [email protected] (G.C.); [email protected] (X.P.); [email protected] (J.W.); [email protected] (Z.W.); [email protected] (B.Z.); [email protected] (W.Z.) 2 Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA * Correspondence: [email protected] or [email protected] † These authors contributed equally to this work. Abstract: Parkinson’s disease (PD) is the most common neurodegenerative movement disorder, characterized by progressive loss of dopaminergic neurons in the substantia nigra, intraneuronal deposition of misfolded proteins known as Lewy bodies, and chronic neuroinflammation. PD can arise from monogenic mutations, but in most cases, the etiology is unclear. Viral infection is gaining increasing attentions as a trigger of PD. In this study, we investigated whether the PD-causative Citation: Ding, Y.; Li, Y.; Chhetri, G.; 620 aspartate (D) to asparagine (N) mutation in the vacuolar protein sorting 35 ortholog (Vps35) Peng, X.; Wu, J.; Wang, Z.; Zhao, B.; precipitated herpes simplex virus (HSV) infection. We observed that ectopic expression of Vps35 Zhao, W.; Li, X. Parkinson’s Disease significantly reduced the proliferation and release of HSV-1 virions; the D620N mutation rendered Causative Mutation in Vps35 Vps35 a partial loss of such inhibitory effects. -
Retromer Deficiency Observed in Alzheimer's Disease Causes
Retromer deficiency observed in Alzheimer’s disease causes hippocampal dysfunction, neurodegeneration, and A accumulation Alim Muhammad*, Ingrid Flores*, Hong Zhang*†, Rui Yu*, Agnieszka Staniszewski*†, Emmanuel Planel*†, Mathieu Herman*†, Lingling Ho‡, Robert Kreber‡, Lawrence S. Honig*§, Barry Ganetzky‡¶, Karen Duff*†, Ottavio Arancio*†, and Scott A. Small*§¶ *Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, and Departments of §Neurology and †Pathology, Columbia University College of Physicians and Surgeons, New York, NY 10032; and ‡Laboratory of Genetics, University of Wisconsin, Madison, WI 53706-1580 Contributed by Barry Ganetzky, March 13, 2008 (sent for review December 2, 2007) Although deficiencies in the retromer sorting pathway have been ␥-secretase, it was important to investigate retromer deficiency linked to late-onset Alzheimer’s disease, whether these deficien- on a nonmutated genetic background. To determine whether cies underlie the disease remains unknown. Here we characterized retromer deficiency causes hippocampal dysfunction, a key two genetically modified animal models to test separate but clinical feature of Alzheimer’s disease, we began by investigating related questions about the effects that retromer deficiency has on retromer deficiency in genetically modified mice. Our results the brain. First, testing for cognitive defects, we investigated suggest that retromer deficiency causes hippocampal dysfunction retromer-deficient mice and found that they develop hippocampal- by elevating concentrations of endogenous A peptide. dependent memory and synaptic dysfunction, which was associ- Although APP and BACE are highly homologous across species, ated with elevations in endogenous A peptide. Second, testing important sequence differences do exist, and these differences can for neurodegeneration and amyloid deposits, we investigated affect their intracellular transport, APP processing, and the neu- retromer-deficient flies expressing human wild-type amyloid pre- rotoxicity of APP end products (12). -
Coordinated Morphogenesis of Neurons and Glia
Available online at www.sciencedirect.com ScienceDirect Coordinated morphogenesis of neurons and glia Elizabeth R Lamkin and Maxwell G Heiman Glia adopt remarkable shapes that are tightly coordinated with The scope of the problem: highly dynamic and the morphologies of their neuronal partners. To achieve these localized morphological changes precise shapes, glia and neurons exhibit coordinated The intimate associations between glia and synapses morphological changes on the time scale of minutes and on exhibit highly dynamic morphological changes on the size scales ranging from nanometers to hundreds of microns. order of minutes [7–11]. Landmark studies using time- Here, we review recent studies that reveal the highly dynamic, lapse confocal imaging of rodent brain slices revealed that localized morphological changes of mammalian neuron–glia post-synaptic dendritic spines and astrocytic processes do contacts. We then explore the power of Drosophila and C. not change shape in perfect register, yet generally grow elegans models to study coordinated changes at defined or shrink together over time [7,9]. Remarkably, this neuron–glia contacts, highlighting the use of innovative genetic coordinated growth is achieved even though glia–spine and imaging tools to uncover the molecular mechanisms interactions undergo rapid structural changes, astrocytic responsible for coordinated morphogenesis of neurons processes tend to exhibit even greater motility than their and glia. dendritic spine counterparts, and the extent of glial coverage of spines varies [7]. Two recent, complementary studies provided evidence for a mechanism that may help to explain the coordinated growth of astrocytic processes and dendritic spines. Address Perez-Alvarez et al. and Bernardinelli et al. -
Parkinson's Disease-Linked D620N VPS35 Knockin Mice Manifest Tau
Parkinson’s disease-linked D620N VPS35 knockin mice manifest tau neuropathology and dopaminergic neurodegeneration Xi Chena, Jennifer K. Kordicha, Erin T. Williamsa, Nathan Levinea, Allyson Cole-Straussb, Lee Marshalla, Viviane Labriea,c, Jiyan Maa, Jack W. Liptonb, and Darren J. Moorea,1 aCenter for Neurodegenerative Science, Van Andel Research Institute, Grand Rapids, MI 49503; bDepartment of Translational Science and Molecular Medicine, Michigan State University, Grand Rapids, MI 49503; and cDivision of Psychiatry and Behavioral Medicine, College of Human Medicine, Michigan State University, Grand Rapids, MI 49503 Edited by Anders Björklund, Lund University, Lund, Sweden, and approved February 13, 2019 (received for review August 30, 2018) Mutations in the vacuolar protein sorting 35 ortholog (VPS35) since only a single D620N mutation carrier has been evaluated at gene represent a cause of late-onset, autosomal dominant familial autopsy but with the notable exception of key PD-relevant brain Parkinson’s disease (PD). A single missense mutation, D620N, is regions (i.e., substantia nigra, locus ceruleus, or any brainstem considered pathogenic based upon its segregation with disease area) (7). Outside of these areas, VPS35 mutation carriers lack in multiple families with PD. At present, the mechanism(s) by extranigral α-synuclein–positive Lewy body pathology (7), a which familial VPS35 mutations precipitate neurodegeneration in characteristic hallmark of PD brains. The mechanism by which PD are poorly understood. Here, we employ a germline D620N dominantly inherited mutations in VPS35 induce neuropathology VPS35 knockin (KI) mouse model of PD to formally establish the and neurodegeneration in PD remains enigmatic. age-related pathogenic effects of the D620N mutation at physiolog- VPS35 encodes a core component of the retromer complex, ical expression levels. -
Down-Regulation of Dendritic Spine and Glutamic Acid Decarboxylase 67 Expressions in the Reelin Haploinsufficient Heterozygous Reeler Mouse
Down-regulation of dendritic spine and glutamic acid decarboxylase 67 expressions in the reelin haploinsufficient heterozygous reeler mouse Wen Sheng Liu*, Christine Pesold*, Miguel A. Rodriguez*, Giovanni Carboni*, James Auta*, Pascal Lacor*, John Larson*, Brian G. Condie†, Alessandro Guidotti*, and Erminio Costa*‡ *Psychiatric Institute, Department of Psychiatry, College of Medicine, University of Illinois, Chicago, IL 60612; and †Institute of Molecular Medicine and Genetics, Departments of Medicine and Cellular Biology and Anatomy, Medical College of Georgia, Augusta, GA 30912 Contributed by Erminio Costa, December 22, 2000 Heterozygous reeler mice (HRM) haploinsufficient for reelin ex- heterozygote reeler mice (HRM) and in heterozygote GAD67 Ϸ press 50% of the brain reelin content of wild-type mice, but are knockout mice (HG67M) and compared them to their respective phenotypically different from both wild-type mice and homozy- wild-type background mice (WTM). In the present study, we gous reeler mice. They exhibit, (i) a down-regulation of glutamic have also quantified the number of neurons immunopositive for acid decarboxylase 67 (GAD67)-positive neurons in some but not reelin in the motor area of the frontoparietal cortex (FPC) of every cortical layer of frontoparietal cortex (FPC), (ii) an increase of HRM, as well as the total number of neurons immunopositive for neuronal packing density and a decrease of cortical thickness NeuN and the number of glial cells stained by Nissl (13) because of neuropil hypoplasia, (iii) a decrease of dendritic spine expressed in each of the six layers of this cortical area. In WTM, expression density on basal and apical dendritic branches of motor HRM, and HG67M, we have also quantified the laminar expres- FPC layer III pyramidal neurons, and (iv) a similar decrease in sion of GAD67-immunopositive neurons and the dendritic spine dendritic spines expressed on the basal dendrite branches of CA1 density expressed by pyramidal neurons of layer III FPC and of pyramidal neurons of the hippocampus.