title: Disruption of Golgi morphology and altered protein glycosylation in PLA2G6-associated neurodegeneration.
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.
authors.affiliation: 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.
authors.forename: Mariska
authors.initials: M
authors.lastname: Davids
authors.affiliation: 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.
authors.forename: Megan S
authors.initials: MS
authors.lastname: Kane
authors.affiliation: 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.
authors.forename: Miao
authors.initials: M
authors.lastname: He
authors.affiliation: 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.
authors.forename: Lynne A
authors.initials: LA
authors.lastname: Wolfe
authors.affiliation: 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.
authors.forename: Xueli
authors.initials: X
authors.lastname: Li
authors.affiliation: 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.
authors.forename: Mohd A
authors.initials: MA
authors.lastname: Raihan
authors.affiliation: 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.
authors.forename: Katherine R
authors.initials: KR
authors.lastname: Chao
authors.affiliation: 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.
authors.forename: William P
authors.initials: WP
authors.lastname: Bone
authors.affiliation: 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.
authors.forename: Cornelius F
authors.initials: CF
authors.lastname: Boerkoel
authors.affiliation: 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.
authors.forename: William A
authors.initials: WA
authors.lastname: Gahl
authors.affiliation: 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.
authors.forename: Camilo
authors.initials: C
authors.lastname: Toro
mesh_terms: D000328:Adult; D002478:Cells, Cultured; D020821:Dystonic Disorders / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D005260:Female; D005347:Fibroblasts / Q000378:metabolism / Q000648:ultrastructure; D006031:Glycosylation; D006056:Golgi Apparatus / Q000378:metabolism / Q000648:ultrastructure*; D054522:Group VI Phospholipases A2 / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007223:Infant; D008297:Male; D009154:Mutation; D019150:Neuroaxonal Dystrophies / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D019636:Neurodegenerative Diseases / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D020734:Parkinsonian Disorders / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D012799:Sialyltransferases / Q000378:metabolism
chemical_list: D012799:Sialyltransferases; D054522:Group VI Phospholipases A2; C516475:PLA2G6 protein, human
keywords: Cell biology; Molecular genetics; Neuromuscular disease