ICP10PK inhibits calpain-dependent release of apoptosis-inducing factor and programmed cell death in response to the toxin MPP+.
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.
Wales
S Q
SQ
Department of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, Baltimore, MD 21201-1559, USA.
Laing
J M
JM
Chen
L
L
Aurelian
L
L
D015655:1-Methyl-4-phenylpyridinium / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis; D051033:Apoptosis Inducing Factor / Q000378:metabolism*; D015415:Biomarkers / Q000032:analysis; D002154:Calpain / Q000037:antagonists & inhibitors; D053148:Caspase 3 / Q000032:analysis; D015870:Gene Expression; D015316:Genetic Therapy / Q000379:methods*; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D015151:Immunoblotting; D020287:In Situ Nick-End Labeling; D008928:Mitochondria / Q000378:metabolism; D016716:PC12 Cells; D010300:Parkinson Disease / Q000235:genetics / Q000628:therapy*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D021381:Protein Transport; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051381:Rats; D012264:Ribonucleotide Reductases / Q000235:genetics*; D015398:Signal Transduction; D014118:Toxins, Biological / Q000494:pharmacology*; D051028:bcl-2-Associated X Protein / Q000378:metabolism
D015655:1-Methyl-4-phenylpyridinium; D051033:Apoptosis Inducing Factor; D015415:Biomarkers; D002154:Calpain; D053148:Caspase 3; D018840:HSP70 Heat-Shock Proteins; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D019253:Proto-Oncogene Proteins c-bcl-2; D012264:Ribonucleotide Reductases; D014118:Toxins, Biological; D051028:bcl-2-Associated X Protein; C100671:ICP10 protein, herpes simplex virus type 2