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Endocrinology. 2009 Dec;150(12):5539-48. doi: 10.1210/en.2009-0640. Epub 2009 Oct 16.

Androgens induce dopaminergic neurotoxicity via caspase-3-dependent activation of protein kinase Cdelta.

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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.


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.

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