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Biomolecules 2015, 5(1), 178-193; doi:10.3390/biom5010178

α-Synuclein-Induced Synapse Damage in Cultured Neurons Is Mediated by Cholesterol-Sensitive Activation of Cytoplasmic Phospholipase A2

1
Department of Pathology and Pathogen Biology, Royal Veterinary College, Hawkshead Lane, North Mymms, Herts AL9 7TA, UK
2
Department of Veterinary Medicine, University of Cambridge, Madingley Road, Cambridge CB3 OES, UK
*
Author to whom correspondence should be addressed.
Academic Editor: Stephan N. Witt
Received: 28 November 2014 / Revised: 11 February 2015 / Accepted: 19 February 2015 / Published: 9 March 2015
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Abstract

The accumulation of aggregated forms of the α-synuclein (αSN) is associated with the pathogenesis of Parkinson’s disease (PD) and Dementia with Lewy Bodies. The loss of synapses is an important event in the pathogenesis of these diseases. Here we show that aggregated recombinant human αSN, but not βSN, triggered synapse damage in cultured neurons as measured by the loss of synaptic proteins. Pre-treatment with the selective cytoplasmic phospholipase A2 (cPLA2) inhibitors AACOCF3 and MAFP protected neurons against αSN-induced synapse damage. Synapse damage was associated with the αSN-induced activation of synaptic cPLA2 and the production of prostaglandin E2. The activation of cPLA2 is the first step in the generation of platelet-activating factor (PAF) and PAF receptor antagonists (ginkgolide B or Hexa-PAF) also protect neurons against αSN-induced synapse damage. αSN-induced synapse damage was also reduced in neurons pre-treated with the cholesterol synthesis inhibitor (squalestatin). These results are consistent with the hypothesis that αSN triggered synapse damage via hyperactivation of cPLA2. They also indicate that αSN-induced activation of cPLA2 is influenced by the cholesterol content of membranes. Inhibitors of this pathway that can cross the blood brain barrier may protect against the synapse damage seen during PD. View Full-Text
Keywords: alpha-synuclein; cholesterol; Parkinson’s disease; phospholipase A2; platelet-activating factor; synapse; synaptophysin alpha-synuclein; cholesterol; Parkinson’s disease; phospholipase A2; platelet-activating factor; synapse; synaptophysin
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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Bate, C.; Williams, A. α-Synuclein-Induced Synapse Damage in Cultured Neurons Is Mediated by Cholesterol-Sensitive Activation of Cytoplasmic Phospholipase A2. Biomolecules 2015, 5, 178-193.

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