TY - JOUR
T1 - TRPM2 promotes neurotoxin MPP+/MPTP-induced cell death
AU - Sun, Yuyang
AU - Sukumaran, Pramod
AU - Selvaraj, Senthil
AU - Cilz, Nicholas I.
AU - Schaar, Anne
AU - Lei, Saobo
AU - Singh, Brij B.
N1 - Funding Information:
Acknowledgments We would like to acknowledge Anthony L. Steichen and Christopher N. Jondle for their help in the flow cytometer analysis and Dr. Yasuo Mori for providing the TRPM2 plasmid. This work was funded by the grant support from the National Institutes of Health (DE017102; DE024300; GM113123) awarded to BBS. The Flow Cytometer core is supported by P20GM103442 and P20GM113123 funded by NIH. The funders (NIH) had no further role in the study design, data analysis, and/or interpretation of the data.
Publisher Copyright:
© Springer Science+Business Media New York 2016.
PY - 2018/1/1
Y1 - 2018/1/1
N2 - Ca2++ is essential for a variety of physiological processes that regulate gene transcription to neuronal growth and their survival. 1-methyl-4-phenyl-1,2,3,6- t e t r a h ydrop y r i d i n e (MPTP) and 1-meth y l - 4 - phenylpyridinium ions (MPP+) are potent neurotoxins that selectively destroys the dopaminergic (DA) neurons and mimics Parkinson’s disease (PD) like symptoms, but the mechanism as how MPP+/MPTP effects DA neuron survival is not well-understood. In the present study, we found that MPP+ treatment increased the level of reactive oxygen species (ROS) that activates and upregulates the expression and function of melastatin-like transient receptor potential (TRPM) subfamily member, melastatin-like transient receptor potential channel 2 (TRPM2). Correspondingly, TRPM2 expression was also increased in substantia nigra of MPTP-induced PD mouse model and PD patients. ROS-mediated activation of TRPM2 resulted in an increased intracellular Ca2++, which in turn promoted cell death in SH-SY5Y cells. Intracellular Ca2++ overload caused by MPP+-induced ROS also affected calpain activity, followed by increased caspase 3 activities and activation of downstream apoptotic pathway. On the other hand, quenching of H2O2 by antioxidants, resveratrol (RSV), or Nacetylcysteine (NAC) effectively blocked TRPM2-mediated Ca2++ influx, decreased intracellular Ca2++ overload, and increased cell survival. Importantly, pharmacological inhibition of TRPM2 or knockdown of TRPM2 using siRNA, but not control siRNA, showed an increased protection by preventing MPP+-induced Ca2++ increase and inhibited apoptosis. Taken together, we show here a novel role for TRPM2 expression and function in MPP+-induced dopaminergic neuronal cell death.
AB - Ca2++ is essential for a variety of physiological processes that regulate gene transcription to neuronal growth and their survival. 1-methyl-4-phenyl-1,2,3,6- t e t r a h ydrop y r i d i n e (MPTP) and 1-meth y l - 4 - phenylpyridinium ions (MPP+) are potent neurotoxins that selectively destroys the dopaminergic (DA) neurons and mimics Parkinson’s disease (PD) like symptoms, but the mechanism as how MPP+/MPTP effects DA neuron survival is not well-understood. In the present study, we found that MPP+ treatment increased the level of reactive oxygen species (ROS) that activates and upregulates the expression and function of melastatin-like transient receptor potential (TRPM) subfamily member, melastatin-like transient receptor potential channel 2 (TRPM2). Correspondingly, TRPM2 expression was also increased in substantia nigra of MPTP-induced PD mouse model and PD patients. ROS-mediated activation of TRPM2 resulted in an increased intracellular Ca2++, which in turn promoted cell death in SH-SY5Y cells. Intracellular Ca2++ overload caused by MPP+-induced ROS also affected calpain activity, followed by increased caspase 3 activities and activation of downstream apoptotic pathway. On the other hand, quenching of H2O2 by antioxidants, resveratrol (RSV), or Nacetylcysteine (NAC) effectively blocked TRPM2-mediated Ca2++ influx, decreased intracellular Ca2++ overload, and increased cell survival. Importantly, pharmacological inhibition of TRPM2 or knockdown of TRPM2 using siRNA, but not control siRNA, showed an increased protection by preventing MPP+-induced Ca2++ increase and inhibited apoptosis. Taken together, we show here a novel role for TRPM2 expression and function in MPP+-induced dopaminergic neuronal cell death.
KW - Apoptosis
KW - Calcium
KW - MPTP/MPP
KW - Oxidative stress
KW - ROS
KW - TRPM2
UR - http://www.scopus.com/inward/record.url?scp=85047298238&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85047298238&partnerID=8YFLogxK
U2 - 10.1007/s12035-016-0338-9
DO - 10.1007/s12035-016-0338-9
M3 - Article
C2 - 27957685
AN - SCOPUS:85047298238
VL - 55
SP - 409
EP - 420
JO - Molecular Neurobiology
JF - Molecular Neurobiology
SN - 0893-7648
IS - 1
ER -