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Original article
Disruption of Golgi morphology and altered protein glycosylation in PLA2G6-associated neurodegeneration
  1. Mariska Davids1,2,
  2. Megan S Kane1,2,
  3. Miao He3,4,
  4. Lynne A Wolfe1,2,
  5. Xueli Li3,4,
  6. Mohd A Raihan3,4,
  7. Katherine R Chao1,2,
  8. William P Bone1,2,
  9. Cornelius F Boerkoel1,2,
  10. William A Gahl1,2,
  11. Camilo Toro1,2
  1. 1NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, NIH, Bethesda, Maryland, USA
  2. 2Office of the Clinical Director, NHGRI, National Institutes of Health, Bethesda, Maryland, USA
  3. 3Department of Pathology and Laboratory of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
  4. 4The Michael J Palmieri Metabolic Laboratory, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
  1. Correspondence to Dr Mariska Davids, National Institutes of Health, UDP Translational Laboratory, 5625 Fishers Lane Room 4N-15, Rockville, MD 20852, USA; mariska.davids{at}nih.gov

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 ionisation - 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.

  • Molecular genetics
  • Cell biology
  • Neuromuscular disease

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