Amyloid beta-peptide(1-42) and hydrogen peroxide-induced toxicity are mediated by TRPM2 in rat primary striatal cultures.
Amyloid beta-peptide (Abeta) 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 Ca(2+)-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 Abeta 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 Abeta-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 Abeta-induced cell death. Furthermore, a small interfering RNA which targets TRPM2, reduced TRPM2 mRNA levels and the toxicity induced by hydrogen peroxide and Abeta. These data demonstrate that activation of TRPM2, functionally expressed in primary cultures of rat striatum, contributes to Abeta- and oxidative stress-induced striatal cell death.
Fonfria
E
E
Neurology and GI CEDD, GlaxoSmithKline Research and Development Limited, Harlow, UK.
Marshall
I C B
IC
Boyfield
I
I
Skaper
S D
SD
Hughes
J P
JP
Owen
D E
DE
Zhang
W
W
Miller
B A
BA
Benham
C D
CD
McNulty
S
S
D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D051152:Clusterin / Q000235:genetics / Q000378:metabolism*; D003342:Corpus Striatum / Q000166:cytology; D006861:Hydrogen Peroxide / Q000633:toxicity*; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D016877:Oxidants / Q000633:toxicity*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D010446:Peptide Fragments / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley
D016229:Amyloid beta-Peptides; D051152:Clusterin; D016877:Oxidants; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D006861:Hydrogen Peroxide; D002118:Calcium