TRPM2 Promotes Neurotoxin MPP + /MPTP-Induced Cell Death

In neurons, Ca 2+ 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-tetrahydropyridine (MPTP) and 1-methyl-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 Ca 2+ , which in turn promoted cell death in SH-SY5Y cells. Intracellular Ca 2+ 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 H 2 O 2 by antioxidants, resveratrol (RSV), or N-acetylcysteine (NAC) effectively blocked TRPM2-mediated Ca 2+ influx, decreased intracellular Ca 2+ 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 Ca 2+ increase and inhibited apoptosis. Taken together, we show here a novel role for TRPM2 expression and function in MPP + -induced dopaminergic neuronal cell death.