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Apoptosis inducing factor mediates caspase‐independent 1‐methyl‐4‐phenylpyridinium toxicity in dopaminergic cells
Author(s) -
Chu Charleen T.,
Zhu Jianhui,
Cao Guodong,
Signore Armando,
Wang Suping,
Chen Jun
Publication year - 2005
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2005.03329.x
Subject(s) - mptp , dopaminergic , apoptosis inducing factor , programmed cell death , neurotoxin , biology , microbiology and biotechnology , apoptosis , caspase , neurotoxicity , dna fragmentation , caspase 3 , toxicity , chemistry , neuroscience , biochemistry , dopamine , organic chemistry
Parkinson's disease is a debilitating neurodegenerative disease characterized by loss of midbrain dopaminergic neurons. These neurons are particularly sensitive to the neurotoxin 1‐methyl‐4‐phenylpyridinium (MPP + ), the active metabolite of 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP), which causes parkinsonian syndromes in humans, monkeys and rodents. Although apoptotic cell death has been implicated in MPTP/MPP + toxicity, several recent studies have challenged the role of caspase‐dependent apoptosis in dopaminergic neurons. Using the midbrain‐derived MN9D dopaminergic cell line, we found that MPP + treatment resulted in an active form of cell death that could not be prevented by caspase inhibitors or over‐expression of a dominant negative inhibitor of apoptotic protease activating factor 1/caspase‐9. Apoptosis inducing factor (AIF) is a mitochondrial protein that may mediate caspase‐independent forms of regulated cell death following its translocation to the nucleus. We found that MPP + treatment elicited nuclear translocation of AIF accompanied by large‐scale DNA fragmentation. To establish the role of AIF in MPP + toxicity, we constructed a DNA vector encoding a short hairpin sequence targeted against AIF. Reduction of AIF expression by RNA interference inhibited large‐scale DNA fragmentation and conferred significant protection against MPP + toxicity. Studies of primary mouse midbrain cultures further supported a role for AIF in caspase‐independent cell death in MPP + ‐treated dopaminergic neurons.