Journal
MOLECULAR NEUROBIOLOGY
Volume 55, Issue 1, Pages 409-420Publisher
SPRINGER
DOI: 10.1007/s12035-016-0338-9
Keywords
TRPM2; Oxidative stress; ROS; Calcium; MPTP/MPP+; Apoptosis
Categories
Funding
- National Institutes of Health [DE017102, DE024300, GM113123]
- NIH [P20GM103442, P20GM113123]
- Office Of The Director
- Office of Integrative Activities [1355466] Funding Source: National Science Foundation
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In neurons, 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-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 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.
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