Inhibition of cytosolic Phospholipase A2 prevents prion peptide-induced neuronal damage and co-localisation with Beta III Tubulin

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Abstract

Background

Activation of phospholipase A ₂ (PLA ₂) and the subsequent metabolism of arachidonic acid (AA) to prostaglandins have been shown to play an important role in neuronal death in neurodegenerative disease. Here we report the effects of the prion peptide fragment HuPrP106-126 on the PLA ₂ cascade in primary cortical neurons and translocation of cPLA ₂ to neurites.

Results

Exposure of primary cortical neurons to HuPrP106-126 increased the levels of phosphorylated cPLA ₂ and caused phosphorylated cPLA ₂ to relocate from the cell body to the cellular neurite in a PrP-dependent manner, a previously unreported observation. HuPrP106-126 also induced significant AA release, an indicator of cPLA ₂ activation; this preceded synapse damage and subsequent cellular death. The novel translocation of p-cPLA ₂ postulated the potential for exposure to HuPrP106-126 to result in a re-arrangement of the cellular cytoskeleton. However p-cPLA ₂ did not colocalise significantly with F-actin, intermediate filaments, or microtubule-associated proteins. Conversely, p-cPLA ₂ did significantly colocalise with the cytoskeletal protein beta III tubulin. Pre-treatment with the PLA ₂ inhibitor, palmitoyl trifluoromethyl ketone (PACOCF ₃) reduced cPLA ₂ activation, AA release and damage to the neuronal synapse. Furthermore, PACOCF ₃ reduced expression of p-cPLA ₂ in neurites and inhibited colocalisation with beta III tubulin, resulting in protection against PrP-induced cell death.

Conclusions

Collectively, these findings suggest that cPLA ₂ plays a vital role in the action of HuPrP106-126 and that the colocalisation of p-cPLA ₂ with beta III tubulin could be central to the progress of neurodegeneration caused by prion peptides. Further work is needed to define exactly how PLA ₂ inhibitors protect neurons from peptide-induced toxicity and how this relates to intracellular structural changes occurring in neurodegeneration.

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Most cited references 57

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cPLA2 is phosphorylated and activated by MAP kinase.

L Lin, M Wartmann, A Y Lin … (1993)

Treatment of cells with agents that stimulate the release of arachidonic acid causes increased serine phosphorylation and activation of cytosolic phospholipase A2 (cPLA2). Here we report that cPLA2 is a substrate for mitogen-activated protein (MAP) kinase. Moreover, phosphorylation by MAP kinase increases the enzymatic activity of cPLA2. The site of cPLA2 phosphorylation by MAP kinase, Ser-505, is identical to the major site of cPLA2 phosphorylation observed in phorbol ester-treated cells. Replacement of Ser-505 with Ala resulted in a mutant cPLA2 that is not a substrate for MAP kinase and causes little or no enhanced agonist-stimulated arachidonate release from intact cells. Taken together, these data indicate that MAP kinase mediates, at least in part, the agonist-induced activation of cPLA2.

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129/Ola mice carrying a null mutation in PrP that abolishes mRNA production are developmentally normal.

J C Manson, A R Clarke, M L Hooper … (1994)

The neural membrane glycoprotein PrP is implicated in the pathogenesis of the transmissible spongiform encephalopathies; however, the normal function of PrP and its precise role in disease are not understood. Recently, gene targeting has been used to produce mice with neo/PrP fusion transcripts, but no detectable PrP protein in the brain (1). Here we report the use of a different targeting strategy, to produce inbred mice with a complete absence of both PrP protein and mRNA sequences. At 7 mo of age, these mice show no overt phenotypic abnormalities despite the normal high levels of expression of PrP during mouse development. The mice are being used in experiments designed to address the role of PrP in the pathogenesis of scrapie and the replication of infectivity.

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Neurotoxicity of a prion protein fragment.

O Bugiani, Mario Salmona, F. Tagliavini … (1993)

The cellular prion protein (PrPC) is a sialoglycoprotein of M(r) 33-35K that is expressed predominantly in neurons. In transmissible and genetic neurodegenerative disorders such as scrapie of sheep, spongiform encephalopathy of cattle and Creutzfeldt-Jakob or Gerstmann-Sträussler-Scheinker diseases of humans, PrPC is converted into an altered form (termed PrPSc) which is distinguishable from its normal homologue by its relative resistance to protease digestion. PrPSc accumulates in the central nervous system of affected individuals, and its protease-resistant core aggregates extracellularly into amyloid fibrils. The process is accompanied by nerve cell loss, whose pathogenesis and molecular basis are not understood. We report here that neuronal death results from chronic exposure of primary rat hippocampal cultures to micromolar concentrations of a peptide corresponding to residues 106-126 of the amino-acid sequence deduced from human PrP complementary DNA. DNA fragmentation of degenerating neurons indicates that cell death occurred by apoptosis. The PrP peptide 106-126 has a high intrinsic ability to polymerize into amyloid-like fibrils in vitro. These findings indicate that cerebral accumulation of PrPSc and its degradation products may play a role in the nerve cell degeneration that occurs in prion-related encephalopathies.

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Author and article information

Journal

Journal ID (nlm-ta): BMC Neurosci

Journal ID (iso-abbrev): BMC Neurosci

Title: BMC Neuroscience

Publisher: BioMed Central

ISSN (Electronic): 1471-2202

Publication date Collection: 2012

Publication date (Electronic): 28 August 2012

Volume: 13

Page: 106

Affiliations

[1 ]Department of Pathology and Infectious Diseases, Royal Veterinary College, Hawkshead Lane, North Mymms, Hertfordshire AL9 7TA, UK

[2 ]Present address: Department of Hematology, Cancer Institute, University College Medical School, London NW3 2PF, UK

[3 ]Present address: Department of Veterinary Medicine, University of Cambridge, Madingley Road, Cambridge CB3 0ES, UK

Article

Publisher ID: 1471-2202-13-106

DOI: 10.1186/1471-2202-13-106

PMC ID: 3496594

PubMed ID: 22928663

SO-VID: d88ab3d0-28ed-423c-a6ed-fdfdcf49db4c

License:

This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

History

Date received : 8 March 2012

Date accepted : 21 August 2012

Product

Self URI: http://www.biomedcentral.com/1471-2202/13/106

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