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 journalArticle

15 Citations (Scopus)

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
Pages (from-to)409-420
Number of pages12
JournalMolecular Neurobiology
Volume55
Issue number1
DOIs
Publication statusPublished - 1 Jan 2018

Fingerprint

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
Neurotoxins
Parkinson Disease
Reactive Oxygen Species
Cell Death
Dopaminergic Neurons
Small Interfering RNA
Physiological Phenomena
Transient Receptor Potential Channels
Calpain
Substantia Nigra
Caspase 3
Cell Survival
Up-Regulation
Antioxidants
Pharmacology
Ions
Apoptosis
Survival
Growth

Keywords

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

ASJC Scopus subject areas

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

Cite this

Sun, Y., Sukumaran, P., Selvaraj, S., Cilz, N. I., Schaar, A., Lei, S., & Singh, B. B. (2018). TRPM2 promotes neurotoxin MPP+/MPTP-induced cell death. Molecular Neurobiology, 55(1), 409-420. https://doi.org/10.1007/s12035-016-0338-9

TRPM2 promotes neurotoxin MPP+/MPTP-induced cell death. / Sun, Yuyang; Sukumaran, Pramod; Selvaraj, Senthil; Cilz, Nicholas I.; Schaar, Anne; Lei, Saobo; Singh, Brij B.

In: Molecular Neurobiology, Vol. 55, No. 1, 01.01.2018, p. 409-420.

Research output: Contribution to journalArticle

Sun, Y, Sukumaran, P, Selvaraj, S, Cilz, NI, Schaar, A, Lei, S & Singh, BB 2018, 'TRPM2 promotes neurotoxin MPP+/MPTP-induced cell death', Molecular Neurobiology, vol. 55, no. 1, pp. 409-420. https://doi.org/10.1007/s12035-016-0338-9
Sun, Yuyang ; Sukumaran, Pramod ; Selvaraj, Senthil ; Cilz, Nicholas I. ; Schaar, Anne ; Lei, Saobo ; Singh, Brij B. / TRPM2 promotes neurotoxin MPP+/MPTP-induced cell death. In: Molecular Neurobiology. 2018 ; Vol. 55, No. 1. pp. 409-420.
@article{261445ac19fa4a27abd991c94740db1b,
title = "TRPM2 promotes neurotoxin MPP+/MPTP-induced cell death",
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.",
keywords = "Apoptosis, Calcium, MPTP/MPP, Oxidative stress, ROS, TRPM2",
author = "Yuyang Sun and Pramod Sukumaran and Senthil Selvaraj and Cilz, {Nicholas I.} and Anne Schaar and Saobo Lei and Singh, {Brij B.}",
year = "2018",
month = "1",
day = "1",
doi = "10.1007/s12035-016-0338-9",
language = "English",
volume = "55",
pages = "409--420",
journal = "Molecular Neurobiology",
issn = "0893-7648",
publisher = "Humana Press",
number = "1",

}

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.

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

VL - 55

SP - 409

EP - 420

JO - Molecular Neurobiology

JF - Molecular Neurobiology

SN - 0893-7648

IS - 1

ER -