TRPM2 promotes neurotoxin MPP+/MPTP-induced cell death

Yuyang Sun, Pramod Sukumaran, Senthil Selvaraj, Nicholas I. Cilz, Anne Schaar, Saobo Lei, Brij B Singh

Research output: Contribution to journalArticlepeer-review

31 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)409-420
Number of pages12
JournalMolecular Neurobiology
Volume55
Issue number1
DOIs
StatePublished - Jan 1 2018
Externally publishedYes

Keywords

  • Apoptosis
  • Calcium
  • MPTP/MPP
  • Oxidative stress
  • ROS
  • TRPM2

ASJC Scopus subject areas

  • Neuroscience (miscellaneous)
  • Neurology
  • Cellular and Molecular Neuroscience

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