Abstract
Apoptosis is a widely accepted component of the pathogenesis of Parkinson's disease (PD), a debilitating neurodegenerative disorder characterized by loss of dopaminergic neurons in the substantia nigra. However, additional death programs were implicated, and current understanding of the cycle of intracellular events that leads to the demise of these neuron Jis limited. Gene therapy strategies were proposed to inhibit apoptosis, but they have met with relatively limited success. Here we report that the antiapoptotic herpes simplex virus type 2 gene ICP10PK protects neuronally differentiated PC12 cells from death caused by 1-methyl-4-phenylpyridinium (in vitro PD model) through inhibition of calpain I activation and the resulting inhibition of Bax translocation to the mitochondria, apoptosis-inducing factor release and caspase-3 activation. Neuroprotection is through ICP10PK-mediated activation of the PI3-K/Akt survival pathway and upregulation/stabilization of the antiapoptotic protein Bcl-2 and the cytoprotective chaperone heat-shock protein 70.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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1-Methyl-4-phenylpyridinium / pharmacology*
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Animals
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Apoptosis
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Apoptosis Inducing Factor / metabolism*
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Biomarkers / analysis
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Calpain / antagonists & inhibitors
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Caspase 3 / analysis
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Gene Expression
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Genetic Therapy / methods*
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HSP70 Heat-Shock Proteins / metabolism
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Immunoblotting
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In Situ Nick-End Labeling
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Mitochondria / metabolism
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PC12 Cells
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Parkinson Disease / genetics
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Parkinson Disease / therapy*
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Phosphatidylinositol 3-Kinases / metabolism
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Protein Serine-Threonine Kinases / genetics*
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Protein Transport
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Proto-Oncogene Proteins c-bcl-2 / metabolism
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Rats
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Ribonucleotide Reductases / genetics*
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Signal Transduction
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Toxins, Biological / pharmacology*
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bcl-2-Associated X Protein / metabolism
Substances
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Apoptosis Inducing Factor
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Biomarkers
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HSP70 Heat-Shock Proteins
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Proto-Oncogene Proteins c-bcl-2
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Toxins, Biological
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bcl-2-Associated X Protein
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ICP10 protein, herpes simplex virus type 2
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Ribonucleotide Reductases
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Protein Serine-Threonine Kinases
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Calpain
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Caspase 3
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1-Methyl-4-phenylpyridinium