Amyloid β-peptide(1-42) and hydrogen peroxide-induced toxicity are mediated by TRPM2 in rat primary striatal cultures

E. Fonfria, I. C.B. Marshall, I. Boyfield, S. D. Skaper, J. P. Hughes, D. E. Owen, W. Zhang, B. A. Miller, C. D. Benham, Shaun McNulty

Research output: Contribution to journalArticle

135 Scopus citations

Abstract

Amyloid β-peptide (Aβ) is the main component of senile plaques which characterize Alzheimer's disease and may induce neuronal death through mechanisms which include oxidative stress. To date, the signalling pathways linking oxidant stress, a component of several neurodegenerative diseases, to cell death in the CNS are poorly understood. Melastatin-like transient receptor potential 2 (TRPM2) is a Ca2+-permeant non-selective cation channel, which responds to increases in oxidative stress levels in the cell and is activated by oxidants such as hydrogen peroxide. We demonstrate here that Aβ and hydrogen peroxide both induce death in cultured rat striatal cells which express TRPM2 endogenously. Transfection with a splice variant that acts as a dominant negative blocker of TRPM2 function (TRPM2-S) inhibited both hydrogen peroxide-and Aβ-induced increases in intracellular-free Ca 2+ and cell death. Functional inhibition of TRPM2 activation by the poly(ADP-ribose)polymerase inhibitor SB-750139, a modulator of intracellular pathways activating TRPM2, attenuated hydrogen peroxide- and Aβ-induced cell death. Furthermore, a small interfering RNA which targets TRPM2, reduced TRPM2 mRNA levels and the toxicity induced by hydrogen peroxide and Aβ. These data demonstrate that activation of TRPM2, functionally expressed in primary cultures of rat striatum, contributes to Aβ- and oxidative stress-induced striatal cell death.

Original languageEnglish (US)
Pages (from-to)715-723
Number of pages9
JournalJournal of neurochemistry
Volume95
Issue number3
DOIs
StatePublished - Nov 14 2005

    Fingerprint

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Cellular and Molecular Neuroscience

Cite this

Fonfria, E., Marshall, I. C. B., Boyfield, I., Skaper, S. D., Hughes, J. P., Owen, D. E., Zhang, W., Miller, B. A., Benham, C. D., & McNulty, S. (2005). Amyloid β-peptide(1-42) and hydrogen peroxide-induced toxicity are mediated by TRPM2 in rat primary striatal cultures. Journal of neurochemistry, 95(3), 715-723. https://doi.org/10.1111/j.1471-4159.2005.03396.x