TRPM2 promotes neurotoxin MPP⁺/MPTP-induced cell death

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.