Faculty Collaboration Database

Alpha-synuclein up-regulation and aggregation during MPP+-induced apoptosis in neuroblastoma cells: intermediacy of transferrin receptor iron and hydrogen peroxide. J Biol Chem 2004 Apr 09;279(15):15240-7

Date

01/27/2004

Pubmed ID

14742448

DOI

10.1074/jbc.M312497200

Scopus ID

2-s2.0-2442494278 (requires institutional sign-in at Scopus site)   122 Citations

Abstract

1-Methyl-4-phenylpyridinium (MPP(+)) is a neurotoxin that causes Parkinson's disease in experimental animals and humans. Despite the fact that intracellular iron was shown to be crucial for MPP(+)-induced apoptotic cell death, the molecular mechanisms for the iron requirement remain unclear. We investigated the role of transferrin receptor (TfR) and iron in modulating the expression of alpha-synuclein (alpha-syn) in MPP(+)-induced oxidative stress and apoptosis. Results show that MPP(+) inhibits mitochondrial complex-1 and aconitase activities leading to enhanced H(2)O(2) generation, TfR expression and alpha-syn expression/aggregation. Pretreatment with cell-permeable iron chelators, TfR antibody (that inhibits TfR-mediated iron uptake), or transfection with glutathione peroxidase (GPx1) enzyme inhibits intracellular oxidant generation, alpha-syn expression/aggregation, and apoptotic signaling as measured by caspase-3 activation. Cells overexpressing alpha-syn exacerbated MPP(+) toxicity, whereas antisense alpha-syn treatment totally abrogated MPP(+)-induced apoptosis in neuroblastoma cells without affecting oxidant generation. The increased cytotoxic effects of alpha-syn in MPP(+)-treated cells were attributed to inhibition of mitogen-activated protein kinase and proteasomal function. We conclude that MPP(+)-induced iron signaling is responsible for intracellular oxidant generation, alpha-syn expression, proteasomal dysfunction, and apoptosis. Relevance to Parkinson's disease is discussed.

Author List

Kalivendi SV, Cunningham S, Kotamraju S, Joseph J, Hillard CJ, Kalyanaraman B

Authors

Cecilia J. Hillard PhD Associate Dean, Center Director, Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin
Balaraman Kalyanaraman PhD Professor in the Biophysics department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

1-Methyl-4-phenylpyridinium
Antioxidants
Apoptosis
Blotting, Western
Caspase 3
Caspases
Cell Line, Tumor
Chelating Agents
Cysteine Endopeptidases
Glutathione Peroxidase
Herbicides
Humans
Hydrogen Peroxide
Iron
MAP Kinase Signaling System
Models, Biological
Multienzyme Complexes
Nerve Tissue Proteins
Neuroblastoma
Oligonucleotides, Antisense
Oxidants
Oxidative Stress
Proteasome Endopeptidase Complex
Receptors, Transferrin
Reverse Transcriptase Polymerase Chain Reaction
Signal Transduction
Synucleins
Time Factors
Transfection
Up-Regulation
alpha-Synuclein