Mariska Davids1, Megan S Kane1, Miao He2, Lynne A Wolfe1, Xueli Li2, Mohd A Raihan2, Katherine R Chao1, William P Bone1, Cornelius F Boerkoel1, William A Gahl1, Camilo Toro1. 1. NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, NIH, Bethesda, Maryland, USA Office of the Clinical Director, NHGRI, National Institutes of Health, Bethesda, Maryland, USA. 2. Department of Pathology and Laboratory of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA The Michael J Palmieri Metabolic Laboratory, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
Abstract
BACKGROUND: Mutations in PLA2G6, which encodes the calcium-independent phospholipase A2 group VI, cause neurodegeneration and diffuse cortical Lewy body formation by a yet undefined mechanism. We assessed whether altered protein glycosylation due to abnormal Golgi morphology might be a factor in the pathology of this disease. METHODS: Three patients presented with PLA2G6-associated neurodegeneration (PLAN); two had infantile neuroaxonal dystrophy (INAD) and one had adult-onset dystonia-parkinsonism. We analysed protein N-linked and O-linked glycosylation in cerebrospinal fluid, plasma, urine, and cultured skin fibroblasts using high performance liquid chromatography (HPLC) and matrix-assisted laser desorption ionization--time of flight/mass spectrometry (MALDI-TOF/MS). We also assessed sialylation and Golgi morphology in cultured fibroblasts by immunofluorescence and performed rescue experiments using a lentiviral vector. RESULTS: The patients with INAD had PLA2G6 mutations NM_003560.2: c.[950G>T];[426-1077dup] and c.[1799G>A];[2221C>T] and the patient with dystonia-parkinsonism had PLA2G6 mutations NM_003560.2: c.[609G>A];[2222G>A]. All three patients had altered Golgi morphology and abnormalities of protein O-linked glycosylation and sialylation in cultured fibroblasts that were rescued by lentiviral overexpression of wild type PLA2G6. CONCLUSIONS: Our findings add altered Golgi morphology, O-linked glycosylation and sialylation defects to the phenotypical spectrum of PLAN; these pathways are essential for correct processing and distribution of proteins. Lewy body and Tau pathology, two neuropathological features of PLAN, could emerge from these defects. Therefore, Golgi morphology, O-linked glycosylation and sialylation may play a role in the pathogenesis of PLAN and perhaps other neurodegenerative disorders. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/
BACKGROUND: Mutations in PLA2G6, which encodes the calcium-independent phospholipase A2group VI, cause neurodegeneration and diffuse cortical Lewy body formation by a yet undefined mechanism. We assessed whether altered protein glycosylation due to abnormal Golgi morphology might be a factor in the pathology of this disease. METHODS: Three patients presented with PLA2G6-associated neurodegeneration (PLAN); two had infantile neuroaxonal dystrophy (INAD) and one had adult-onset dystonia-parkinsonism. We analysed protein N-linked and O-linked glycosylation in cerebrospinal fluid, plasma, urine, and cultured skin fibroblasts using high performance liquid chromatography (HPLC) and matrix-assisted laser desorption ionization--time of flight/mass spectrometry (MALDI-TOF/MS). We also assessed sialylation and Golgi morphology in cultured fibroblasts by immunofluorescence and performed rescue experiments using a lentiviral vector. RESULTS: The patients with INAD had PLA2G6 mutations NM_003560.2: c.[950G>T];[426-1077dup] and c.[1799G>A];[2221C>T] and the patient with dystonia-parkinsonism had PLA2G6 mutations NM_003560.2: c.[609G>A];[2222G>A]. All three patients had altered Golgi morphology and abnormalities of protein O-linked glycosylation and sialylation in cultured fibroblasts that were rescued by lentiviral overexpression of wild type PLA2G6. CONCLUSIONS: Our findings add altered Golgi morphology, O-linked glycosylation and sialylation defects to the phenotypical spectrum of PLAN; these pathways are essential for correct processing and distribution of proteins. Lewy body and Tau pathology, two neuropathological features of PLAN, could emerge from these defects. Therefore, Golgi morphology, O-linked glycosylation and sialylation may play a role in the pathogenesis of PLAN and perhaps other neurodegenerative disorders. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/
Authors: Jennifer J Johnston; Jamie K Teer; Praveen F Cherukuri; Nancy F Hansen; Stacie K Loftus; Karen Chong; James C Mullikin; Leslie G Biesecker Journal: Am J Hum Genet Date: 2010-05-06 Impact factor: 11.025
Authors: Jamie K Teer; Lori L Bonnycastle; Peter S Chines; Nancy F Hansen; Natsuyo Aoyama; Amy J Swift; Hatice Ozel Abaan; Thomas J Albert; Elliott H Margulies; Eric D Green; Francis S Collins; James C Mullikin; Leslie G Biesecker Journal: Genome Res Date: 2010-09-01 Impact factor: 9.043
Authors: A Gregory; S K Westaway; I E Holm; P T Kotzbauer; P Hogarth; S Sonek; J C Coryell; T M Nguyen; N Nardocci; G Zorzi; D Rodriguez; I Desguerre; E Bertini; A Simonati; B Levinson; C Dias; C Barbot; I Carrilho; M Santos; I Malik; J Gitschier; S J Hayflick Journal: Neurology Date: 2008-09-17 Impact factor: 9.910
Authors: Andreas Gnirke; Alexandre Melnikov; Jared Maguire; Peter Rogov; Emily M LeProust; William Brockman; Timothy Fennell; Georgia Giannoukos; Sheila Fisher; Carsten Russ; Stacey Gabriel; David B Jaffe; Eric S Lander; Chad Nusbaum Journal: Nat Biotechnol Date: 2009-02-01 Impact factor: 54.908
Authors: Timothy Gall; Elise Valkanas; Christofer Bello; Thomas Markello; Christopher Adams; William P Bone; Alexander J Brandt; Jennifer M Brazill; Lynn Carmichael; Mariska Davids; Joie Davis; Zoraida Diaz-Perez; David Draper; Jeremy Elson; Elise D Flynn; Rena Godfrey; Catherine Groden; Cheng-Kang Hsieh; Roxanne Fischer; Gretchen A Golas; Jessica Guzman; Yan Huang; Megan S Kane; Elizabeth Lee; Chong Li; Amanda E Links; Valerie Maduro; May Christine V Malicdan; Fayeza S Malik; Michele Nehrebecky; Joun Park; Paul Pemberton; Katherine Schaffer; Dimitre Simeonov; Murat Sincan; Damian Smedley; Zaheer Valivullah; Colleen Wahl; Nicole Washington; Lynne A Wolfe; Karen Xu; Yi Zhu; William A Gahl; Cynthia J Tifft; Camillo Toro; David R Adams; Miao He; Peter N Robinson; Melissa A Haendel; R Grace Zhai; Cornelius F Boerkoel Journal: Front Med (Lausanne) Date: 2017-05-26
Authors: Megan S Kane; Mariska Davids; Michelle R Bond; Christopher J Adams; Megan E Grout; Ian G Phelps; Diana R O'Day; Jennifer C Dempsey; Xeuli Li; Gretchen Golas; Gilbert Vezina; Meral Gunay-Aygun; John A Hanover; Dan Doherty; Miao He; May Christine V Malicdan; William A Gahl; Cornelius F Boerkoel Journal: Cilia Date: 2017-03-23
Authors: Ranjani Ganapathy S; Kateřina Levová; Lenka Kotačková; Jiří Trnka; David Zogala; Jan Rusz; Tomáš Zima; David Devos; Karel Šonka; Evžen Růžička; Marta Kalousová; Petr Dušek Journal: Mov Disord Date: 2022-02-07 Impact factor: 9.698
Authors: Jacqueline Alexander; April M Teague; Jing Chen; Christopher E Aston; Yuet-Kin Leung; Steven Chernausek; Rebecca A Simmons; Sara E Pinney Journal: PLoS One Date: 2018-02-22 Impact factor: 3.752