Androgens induce dopaminergic neurotoxicity via caspase-3-dependent activation of protein kinase Cdelta.
Aged men have a greater incidence of Parkinson's disease (PD) than women. PD is a neurodegenerative condition associated with the loss of dopamine neurons in the nigrostriatal pathway. This study examined the neurotoxic effects of androgens in a dopaminergic cell line (N27 cells) and the downstream signaling pathways activated by androgens. Treatment of N27 cells with testosterone- and dihydrotestosterone-induced mitochondrial dysfunction, protein kinase C (PKC)-delta cleavage, and apoptosis in dopaminergic neuronal cells. Inhibition of caspase-3 prevented the cleavage of PKCdelta from the full-length element to the catalytic fragment and apoptosis in N27 cells, suggesting that androgen-induced apoptosis is mediated by caspase-3-dependent activation of PKCdelta. Androgen-induced apoptosis may be specific to dopamine neurons as evidenced by a lack of testosterone-induced apoptosis in GnRH neurons. These results support a neurotoxic consequence of testosterone on dopaminergic neurons and may provide insight into the gender bias found in PD.
Cunningham
Rebecca L
RL
Department of Pharmacology and the Sam and Ann Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center, San Antonio, Texas 78229, USA. bcunning@hsc.unt.edu
Giuffrida
Andrea
A
Roberts
James L
JL
D000728:Androgens / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D053148:Caspase 3 / Q000378:metabolism*; D061945:Caspase Inhibitors; D002460:Cell Line; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D005485:Flutamide / Q000494:pharmacology; D008297:Male; D008856:Microscopy, Fluorescence; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D009842:Oligopeptides / Q000494:pharmacology; D054464:Peroxiredoxins / Q000378:metabolism; D051745:Protein Kinase C-delta / Q000378:metabolism*; D051381:Rats; D011944:Receptors, Androgen / Q000378:metabolism; D013739:Testosterone / Q000494:pharmacology
D000728:Androgens; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; D009842:Oligopeptides; D011944:Receptors, Androgen; C110772:benzoylcarbonyl-aspartyl-glutamyl-valyl-aspartyl-fluoromethyl ketone; D013739:Testosterone; D005485:Flutamide; D054464:Peroxiredoxins; D051745:Protein Kinase C-delta; D053148:Caspase 3; D004298:Dopamine