α-Synuclein-induced synapse damage in cultured neurons is mediated by cholesterol-sensitive activation of cytoplasmic phospholipase A2

Biomolecules. 2015 Mar 9;5(1):178-93. doi: 10.3390/biom5010178.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • Cholesterol / metabolism*
  • Cyclooxygenase Inhibitors / pharmacology
  • Enzyme Activation / drug effects
  • Humans
  • Mice
  • Neurons / drug effects*
  • Neurons / enzymology
  • Neurons / metabolism*
  • Neurons / pathology
  • Neuroprotective Agents / pharmacology
  • Phospholipases A2, Cytosolic / antagonists & inhibitors
  • Phospholipases A2, Cytosolic / metabolism*
  • Platelet Activating Factor / antagonists & inhibitors
  • Protein Aggregates
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / pharmacology
  • Signal Transduction / drug effects
  • Synapses / drug effects*
  • Synapses / enzymology
  • Synapses / metabolism
  • Synapses / pathology*
  • alpha-Synuclein / chemistry
  • alpha-Synuclein / pharmacology*

Substances

  • Cyclooxygenase Inhibitors
  • Neuroprotective Agents
  • Platelet Activating Factor
  • Protein Aggregates
  • Recombinant Proteins
  • SNCA protein, human
  • alpha-Synuclein
  • Cholesterol
  • Phospholipases A2, Cytosolic