P2X7 receptor is critical in α-synuclein--mediated microglial NADPH oxidase activation

Neurobiol Aging. 2015 Jul;36(7):2304-2318. doi: 10.1016/j.neurobiolaging.2015.03.015. Epub 2015 Apr 7.

Abstract

Activated microglia are commonly observed in individuals with neurodegenerative disorders, including Parkinson's disease (PD) and are believed to contribute to neuronal death. This process occurs at least due partially to nicotinamide adenine dinucleotide phosphate oxidase (PHOX) activation, which leads to the production of superoxide and oxidative stress. α-Synuclein (α-Syn), a key protein implicated in PD pathogenesis, can activate microglia, contributing to death of dopaminergic neurons. Here, microglial cells (BV2) and primary cultured microglia were used to study the role that the purinergic receptor P2X7 plays in recognizing α-Syn and promoting PHOX activation. We demonstrate that both wild type and A53T mutant α-Syn readily activate PHOX, with the A53T form producing more rapid and sustained effects,that is, oxidative stress and cellular injuries. Furthermore, this process involves the activation of phosphoinositide 3-kinase (PI3K)/AKT (protein kinase B) pathway. Thus, it is concluded that stimulation of the microglial P2X7 receptor by extracellular α-Syn, with PI3K/AKT activation and increased oxidative stress, could be an important mechanism and a potential therapeutic target for PD.

Keywords: Microglia; P2X7 receptor; PI3K/AKT signaling; Parkinson's disease; α-Synuclein.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Death / genetics
  • Cells, Cultured
  • Dopaminergic Neurons / pathology
  • Enzyme Activation / genetics*
  • Male
  • Membrane Glycoproteins / metabolism
  • Mice, Inbred C57BL
  • Microglia / enzymology*
  • Molecular Targeted Therapy
  • Mutation
  • NADPH Oxidase 2
  • NADPH Oxidases / metabolism*
  • Oxidative Stress / genetics
  • Parkinson Disease / genetics
  • Parkinson Disease / therapy
  • Phosphatidylinositol 3-Kinases / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism
  • Receptors, Purinergic P2X7 / physiology*
  • Signal Transduction / genetics
  • Signal Transduction / physiology
  • alpha-Synuclein / genetics
  • alpha-Synuclein / physiology*

Substances

  • Membrane Glycoproteins
  • Receptors, Purinergic P2X7
  • alpha-Synuclein
  • CYBB protein, human
  • NADPH Oxidase 2
  • NADPH Oxidases
  • neutrophil cytosolic factor 1
  • Phosphatidylinositol 3-Kinases
  • Proto-Oncogene Proteins c-akt