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Zareen Amtul, Jun Yang, Simona Nikolova, Ting-Yim Lee, Robert Bartha, David F Cechetto
Defect in brain microperfusion is increasingly recognized as an antecedent event to Alzheimer's disease (AD) and ischemia. Nevertheless, studies on the role of impaired microperfusion as a pathological trigger to neuroinflammation, Aβ deposition as well as blood-brain barrier (BBB) disruption, and the etiological link between AD and ischemia are lacking. In this study, we employ in vivo sequential magnetic resonance imaging (MRI) and computed tomography (CT) imaging in a co-morbid rat model of β-amyloid toxicity (Aβ) and ischemia (ET1) with subsequent histopathology of striatal lesion core and penumbra at 1, 7, and 28 days post injury...
March 5, 2018: Molecular Neurobiology
Ryuta Nishihara, Kazuhiro Kobayashi, Reiko Imae, Hiroki Tsumoto, Hiroshi Manya, Mamoru Mizuno, Motoi Kanagawa, Tamao Endo, Tatsushi Toda
Dystroglycanopathies are a group of muscular dystrophies that are caused by abnormal glycosylation of dystroglycan; currently 18 causative genes are known. Functions of the dystroglycanopathy genes fukutin, fukutin-related protein (FKRP), and transmembrane protein 5 (TMEM5) were most recently identified; fukutin and FKRP are ribitol-phosphate transferases and TMEM5 is a ribitol xylosyltransferase. In this study, we show that fukutin, FKRP, and TMEM5 form a complex while maintaining each of their enzyme activities...
February 22, 2018: Biochemical and Biophysical Research Communications
Kayla Thompson, Jonathan Chen, Qianyi Luo, Yucheng Xiao, Theodore R Cummins, Ashay D Bhatwadekar
Diabetic retinopathy (DR) is a major cause of adult blindness. Retinal Müller cells maintain water homeostasis and potassium concentration via inwardly rectifying Kir4.1 channels. Accumulation of advanced glycation end products (AGEs) is a major pathologic event in DR. While diabetes leads to a decrease in the Kir4.1 channels, it remains unknown whether AGEs-linked to the basement membrane (BM) affect normal Kir4.1 channels. For this study, we hypothesized that AGE-modification of laminin is detrimental to Kir4...
2018: PloS One
Magda Gioia, Giovanni Francesco Fasciglione, Diego Sbardella, Francesca Sciandra, MariaLuisa Casella, Serena Camerini, Marco Crescenzi, Alessandro Gori, Umberto Tarantino, Paola Cozza, Andrea Brancaccio, Massimo Coletta, Manuela Bozzi
Dystroglycan (DG) is a membrane receptor, belonging to the dystrophin-glycoprotein complex (DGC) and formed by two subunits, α-dystroglycan (α-DG) and β-dystroglycan (β -DG). The C-terminal domain of α-DG and the N-terminal extracellular domain of β -DG are connected, providing a link between the extracellular matrix and the cytosol. Under pathological conditions, such as cancer and muscular dystrophies, DG may be the target of metalloproteinases MMP-2 and MMP-9, contributing to disease progression. Previously, we reported that the C-terminal domain α-DG (483-628) domain is particularly susceptible to the catalytic activity of MMP-2; here we show that the α-DG 621-628 region is required to carry out its complete digestion, suggesting that this portion may represent a MMP-2 anchoring site...
2018: PloS One
Carmen Haro, Mary Luz Uribe, Cristina Quereda, Jesús Cruces, José Martín-Nieto
Purpose: Dystroglycanopathies are a heterogeneous group of recessive neuromuscular dystrophies that affect the muscle, brain and retina, and are caused by deficiencies in the O-glycosylation of α-dystroglycan. This post-translational modification is essential for the formation and maintenance of ribbon synapses in the retina. Fukutin and fukutin-related protein (FKRP) are two glycosyltransferases whose deficiency is associated with severe dystroglycanopathies. These enzymes carry out in vitro the addition of a tandem ribitol 5-phosphate moiety to the so-called core M3 phosphotrisaccharide of α-dystroglycan...
2018: Molecular Vision
Motoi Kanagawa, Tatsushi Toda
Glycosylation is a crucial posttranslational modification that is involved in numerous biological events. Therefore, abnormal glycosylation can impair the functions of glycoproteins or glycolipids and is occasionally associated with cell dysfunction and human diseases. For example, aberrant glycosylation of dystroglycan, a cellular receptor for matrix and synaptic proteins, is associated with muscular dystrophy and lissencephaly. Dystroglycan sugar chains are required for high-affinity binding to ligand proteins, and thus disruption of dystroglycan-ligand linkages underlies disease conditions...
January 31, 2018: Journal of Biochemistry
Keiu Kask, Laura Tikker, Katrin Ruisu, Sirje Lulla, Eva-Maria Oja, Riho Meier, Raivo Raid, Teet Velling, Tambet Tõnissoo, Margus Pooga
Autosomal recessive disorders such as Fukuyama congenital muscular dystrophy, Walker-Warburg syndrome, and the muscle-eye-brain disease are characterized by defects in the development of patient's brain, eyes, and skeletal muscles. These syndromes are accompanied by brain malformations like type II lissencephaly in the cerebral cortex with characteristic overmigrations of neurons through the breaches of the pial basement membrane. The signaling pathways activated by laminin receptors, dystroglycan and integrins, control the integrity of the basement membrane, and their malfunctioning may underlie the pathologies found in the rise of defects reminiscent of these syndromes...
January 30, 2018: Developmental Neurobiology
Felipe Aguayo, Anibal Pacheco, Gonzalo J García Rojo, Javier Pizarro-Bauerle, Ana Doberti, Macarena Tejos, Alexandra García-Pérez, Paulina Rojas, Jenny L Fiedler
A single stress exposure facilitates memory formation through neuroplastic processes that reshape excitatory synapses in the hippocampus, probably requiring changes in extracellular matrix components. We tested the hypothesis that matrix metalloproteinase 9 (MMP-9), an enzyme that degrades components of extracellular matrix and synaptic proteins such as β-dystroglycan (β-DG43), change their activity and distribution in rat hippocampus during the acute stress response. After 2.5 h of restraint stress we found that: i) MMP-9 levels and potential activity increase in whole hippocampal extracts; accompanied by β-DG43 cleavage, and ii) a significant enhancement of MMP-9 immunoreactivity in dendritic fields such as stratum radiatum and molecular layer of hippocampus...
January 23, 2018: ACS Chemical Neuroscience
Atsushi Sudo, Motoi Kanagawa, Mai Kondo, Chiyomi Ito, Kazuhiro Kobayashi, Mitsuharu Endo, Yasuhiro Minami, Atsu Aiba, Tatsushi Toda
Congenital muscular dystrophies (CMDs) are characterized by progressive weakness and degeneration of skeletal muscle. In several forms of CMD, abnormal glycosylation of α-dystroglycan (α-DG) results in conditions collectively known as dystroglycanopathies, which are associated with central nervous system involvement. We recently demonstrated that fukutin, the gene responsible for Fukuyama congenital muscular dystrophy, encodes the ribitol-phosphate transferase essential for dystroglycan function. Brain pathology in patients with dystroglycanopathy typically includes cobblestone lissencephaly, mental retardation, and refractory epilepsy; however, some patients exhibit average intelligence, with few or almost no structural defects...
January 19, 2018: Human Molecular Genetics
Zvi Leibovitz, Hanna Mandel, Tzipora C Falik-Zaccai, Shani Ben Harouch, David Savitzki, Karina Krajden-Haratz, Liat Gindes, Mordechai Tamarkin, Dorit Lev, William B Dobyns, Tally Lerman-Sagie
OBJECTIVES: To elaborate the imaging phenotype associated with a homozygous c.743C > del frameshift mutation in DAG1 leading to complete absence of both α- and β-dystroglycan previously reported in a consanguineous Israeli-Arab family. METHODS: We analyzed prenatal and postnatal imaging data of patients from a consanguineous Israeli-Arab kindred harboring the DAG1 mutation. RESULTS: The imaging studies (fetal ultrasound, CT scan and postnatal MRI) demonstrated: flat cortex (abnormally thick with irregular pebbled cortical-white matter border on MRI), hydrocephalus, scattered small periventricular heterotopia and subependymal hemorrhages and calcifications, z-shaped brainstem, and in addition an occipital encephalocele, vermian agenesis, and an elongated and thick tectum (tectocerebellar dysraphia)...
December 26, 2017: European Journal of Paediatric Neurology: EJPN
Anthony Blaeser, Hiroyuki Awano, Pei Lu, Qi-Long Lu
The glycosylation of alpha-dystroglycan (α-DG) is crucial in maintaining muscle cell membrane integrity. Dystroglycanopathies are identified by the loss of this glycosylation leading to a breakdown of muscle cell membrane integrity and eventual degeneration. However, a small portion of fibers expressing functionally glycosylated α-DG (F-α-DG) (revertant fibers, RF) have been identified. These fibers are generally small in size, centrally nucleated and linked to regenerating fibers. Examination of different muscles have shown various levels of RFs but it is unclear the extent of which they are present...
2018: PloS One
Christine E Hulseberg, Lucie Fénéant, Katarzyna M Szymańska, Judith M White
Lassa virus (LASV) is an arenavirus whose entry into host cells is mediated by a glycoprotein complex (GPC) comprised of a receptor binding subunit, GP1, a fusogenic transmembrane subunit, GP2, and a stable signal peptide. After receptor-mediated internalization, arenaviruses converge in the endocytic pathway, where they are thought to undergo low-pH-triggered, GPC-mediated fusion with a late endosome membrane. A unique feature of LASV entry is a pH-dependent switch from a primary cell surface receptor (α-dystroglycan) to an endosomal receptor, lysosomal-associated membrane protein (Lamp1)...
January 2, 2018: MBio
Reza Maroofian, Moniek Riemersma, Lucas T Jae, Narges Zhianabed, Marjolein H Willemsen, Willemijn M Wissink-Lindhout, Michèl A Willemsen, Arjan P M de Brouwer, Mohammad Yahya Vahidi Mehrjardi, Mahmoud Reza Ashrafi, Benno Kusters, Tjitske Kleefstra, Yalda Jamshidi, Mojila Nasseri, Rolph Pfundt, Thijn R Brummelkamp, Mohammad Reza Abbaszadegan, Dirk J Lefeber, Hans van Bokhoven
BACKGROUND: The phenotypic severity of congenital muscular dystrophy-dystroglycanopathy (MDDG) syndromes associated with aberrant glycosylation of α-dystroglycan ranges from the severe Walker-Warburg syndrome or muscle-eye-brain disease to mild, late-onset, isolated limb-girdle muscular dystrophy without neural involvement. However, muscular dystrophy is invariably found across the spectrum of MDDG patients. METHODS: Using linkage mapping and whole-exome sequencing in two families with an unexplained neurodevelopmental disorder, we have identified homozygous and compound heterozygous mutations in B3GALNT2...
December 22, 2017: Genome Medicine
P Y K Van den Bergh, Y Sznajer, V Van Parys, W van Tol, R A Wevers, D J Lefeber, L Xu, M Lek, D G MacArthur, K Johnson, L Phillips, A Töpf, V Straub
No abstract text is available yet for this article.
December 12, 2017: Neuromuscular Disorders: NMD
Chih-Hung Chen, Ben-Chung Cheng, Kuan-Hung Chen, Pei-Lin Shao, Pei-Hsun Sung, Hsin-Ju Chiang, Chih-Chao Yang, Kun-Chen Lin, Cheuk-Kwan Sun, Jiunn-Jye Sheu, Hsueh-Wen Chang, Mel S Lee, Hon-Kan Yip
Combined therapy with exendin-4 (Ex4) and allogenic adipose-derived mesenchymal stem cells (ADMSC) was tested against either therapy alone for protecting kidney function against chronic kidney disease (CKD) complicated by sepsis syndrome (SS) [i.e., by intraperitoneal injection of cecal-derived bacteria (1.0 × 104) cells/milliliter/total 5.0 cc].Adult-male-Sprague Dawley rats (n=36) were equally divided into group 1 (sham-control), group 2 (CKD), group 3 (CKD-SS), group 4 (CKD-SS-Ex4), group 5 (CKD-SS-ADMSC) and group 6 (CKD-SS-Ex4-ADMSC)...
November 21, 2017: Oncotarget
Chiara Fedeli, Giulia Torriani, Clara Galan-Navarro, Marie-Laurence Moraz, Hector Moreno, Gisa Gerold, Stefan Kunz
Fatal infection with the highly pathogenic Lassa virus (LASV) is characterized by extensive viral dissemination, indicating broad tissue tropism. The major cellular receptor for LASV is the highly conserved extracellular matrix receptor dystroglycan (DG). Binding of LASV depends on DG's tissue-specific post-translational modification with the unusual O-linked polysaccharide matriglycan. Interestingly, functional glycosylation of DG does not always correlate with viral tropism observed in vivo The broadly expressed phosphatidylserine (PS) receptors Axl and Tyro3 were recently identified as alternative LASV receptor candidates...
December 13, 2017: Journal of Virology
Peter D Yurchenco, Karen K McKee, Judith R Reinhard, Markus A Rüegg
Laminins are large heterotrimers composed of the α, β and γ subunits with distinct tissue-specific and developmentally regulated expression patterns. The laminin-α2 subunit, encoded by the LAMA2 gene, is expressed in skeletal muscle, Schwann cells of the peripheral nerve and astrocytes and pericytes of the capillaries in the brain. Mutations in LAMA2 cause the most common type of congenital muscular dystrophies, called LAMA2 MD or MDC1A. The disorder manifests mostly as a muscular dystrophy but slowing of nerve conduction contributes to the disease...
November 27, 2017: Matrix Biology: Journal of the International Society for Matrix Biology
Griselda Vélez-Aguilera, Juan de Dios Gómez-López, Guadalupe E Jiménez-Gutiérrez, Alejandra Vásquez-Limeta, Marco S Laredo-Cisneros, Pablo Gómez, Steve J Winder, Bulmaro Cisneros
β-Dystroglycan (β-DG) is a plasma membrane protein that has ability to target to the nuclear envelope (NE) to maintain nuclear architecture. Nevertheless, mechanisms controlling β-DG nuclear localization and the physiological consequences of a failure of trafficking are largely unknown. We show that β-DG has a nuclear export pathway in myoblasts that depends on the recognition of a nuclear export signal located in its transmembrane domain, by CRM1. Remarkably, NES mutations forced β-DG nuclear accumulation resulting in mislocalization and decreased levels of emerin and lamin B1 and disruption of various nuclear processes in which emerin (centrosome-nucleus linkage and β-catenin transcriptional activity) and lamin B1 (cell cycle progression and nucleoli structure) are critically involved...
February 2018: Biochimica et Biophysica Acta
Kaleb M Naegeli, Eric Hastie, Aastha Garde, Zheng Wang, Daniel P Keeley, Kacy L Gordon, Ariel M Pani, Laura C Kelley, Meghan A Morrissey, Qiuyi Chi, Bob Goldstein, David R Sherwood
Invasive cells use small invadopodia to breach basement membrane (BM), a dense matrix that encases tissues. Following the breach, a large protrusion forms to clear a path for tissue entry by poorly understood mechanisms. Using RNAi screening for defects in Caenorhabditis elegans anchor cell (AC) invasion, we found that UNC-6(netrin)/UNC-40(DCC) signaling at the BM breach site directs exocytosis of lysosomes using the exocyst and SNARE SNAP-29 to form a large protrusion that invades vulval tissue. Live-cell imaging revealed that the protrusion is enriched in the matrix metalloprotease ZMP-1 and transiently expands AC volume by more than 20%, displacing surrounding BM and vulval epithelium...
November 20, 2017: Developmental Cell
Francesca Sciandra, Bianca Maria Scicchitano, Giulia Signorino, Maria Giulia Bigotti, Barbara Tavazzi, Francesca Lombardi, Manuela Bozzi, Gigliola Sica, Bruno Giardina, Sandra Blaess, Andrea Brancaccio
OBJECTIVE: Dystroglycan (DG) is an adhesion complex formed by two subunits, α-DG and β-DG. In skeletal muscle, DG is part of the dystrophin-glycoprotein complex that is crucial for sarcolemma stability and it is involved in a plethora of muscular dystrophy phenotypes. Due to the important role played by DG in skeletal muscle stability as well as in a wide variety of other tissues including brain and the peripheral nervous system, it is essential to investigate its genetic assembly and transcriptional regulation...
November 21, 2017: BMC Research Notes
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