Abstract Title

THE EFFECTS OF ANDROGENS ON CASPASE-1 MEDIATED SIGNALING IN OXIDATIVE STRESSED DOPAMINE NEURONS

Presenter Name

Shaletha Holmes

Abstract

Parkinson’s disease (PD), a neurodegenerative disorder characterized by oxidative stress and the loss of dopamine neurons in the midbrain, affects the aging population. In fact, males have a higher risk for PD than females. While the mechanisms remain elusive, one possibility may be that androgens, such as testosterone, play a potential role. Our studies suggest that androgens can increase the expression of Caspase-1, an enzyme whose activity increases with oxidative stress and can result in mitochondrial collapse, ubiquitination, alpha-synuclein–positive lewy body accumulation, inflammation and apoptosis. Therefore, we hypothesize that in oxidative stress conditions, androgens suppress KLF4, a negative regulator of caspase-1, resulting in the increase of Caspase-1 to promote toxic protein accumulation, inflammation, and apoptotic neuronal cell death. This study is related to the role of testosterone in high levels of oxidative stress associated with aging.

Presentation Type

Oral

Purpose (a):

Oxidative stress and an extensive loss of dopamine neurons in the nigrostriatal pathway are hallmarks of Parkinson’s disease (PD), a neurodegenerative disorder affecting millions of people. Males have a higher risk for PD than females. While the mechanisms remain elusive, one possibility may be that androgens, such as testosterone, play a potential role. Our studies suggest that androgens can increase the expression of Caspase-1, an enzyme whose activity increases with oxidative stress and can result in mitochondrial collapse, ubiquitination, alpha-synuclein–positive lewy body accumulation, inflammation and apoptosis. We hypothesize that in oxidative stress conditions, androgens suppress KLF4, a negative regulator of caspase-1, resulting in overexpression of Caspase-1 leading to toxic protein accumulation, inflammation, and apoptosis.

Methods (b):

We exposed a dopaminergic cell line (N27 cells) to a sublethal concentration of the pro-oxidant, tert-butyl hydrogen peroxide (H2O2) for 24 hrs and assessed cell viability in the presence or absence of testosterone.

Results (c):

Physiologically relevant concentrations of testosterone (0, 1, 10, 100 nM) failed to compromise cell viability in non-oxidatively stressed cells1. In contrast, testosterone did promote cell death in the H2O2 pre-treated cells. In H202 treated cells, testosterone increased caspase-1 expression and activation, as evidenced by an increase in cleaved caspase-1. In addition, KLF4 expression was decreased by testosterone in H2O2 treated cells. The role of KLF4 as a negative regulator of caspase-1 was confirmed in experiments showing that siRNA-mediated knockdown of KLF4 increased caspase-1 levels in H2O2 treated cells. Testosterone increased H202 mediated expression of COX2 signaling, a protein associated with inflammation. Also, testosterone decreased H2O2-induced ubiquitin expression resulting in the accumulation of toxic proteins. Further, testosterone increased H202 induced in apoptosis.

Conclusions (d):

Overall, these results indicate that androgens such as testosterone exert negative effects under oxidative stress conditions through the suppression of KLF4 and activation of caspase-1 signaling pathways leading to cell death. Thus, supporting a role for androgens for the gender bias observed in PD.

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THE EFFECTS OF ANDROGENS ON CASPASE-1 MEDIATED SIGNALING IN OXIDATIVE STRESSED DOPAMINE NEURONS

Parkinson’s disease (PD), a neurodegenerative disorder characterized by oxidative stress and the loss of dopamine neurons in the midbrain, affects the aging population. In fact, males have a higher risk for PD than females. While the mechanisms remain elusive, one possibility may be that androgens, such as testosterone, play a potential role. Our studies suggest that androgens can increase the expression of Caspase-1, an enzyme whose activity increases with oxidative stress and can result in mitochondrial collapse, ubiquitination, alpha-synuclein–positive lewy body accumulation, inflammation and apoptosis. Therefore, we hypothesize that in oxidative stress conditions, androgens suppress KLF4, a negative regulator of caspase-1, resulting in the increase of Caspase-1 to promote toxic protein accumulation, inflammation, and apoptotic neuronal cell death. This study is related to the role of testosterone in high levels of oxidative stress associated with aging.