Abstract
Sex differences are considered predictive factors in the development of several neurological diseases, which are also known to coincide with impaired phosphoinositide 3-kinase (PI3K)-AKT pathway activity, an essential signaling cascade involved in the control of several cellular functions such as autophagy and apoptosis. Here, under physiological conditions, we show important sex differences in the underlying balancing mechanisms that lead to similar AKT activity levels and autophagy and apoptosis processes in the two sexes. We demonstrate inverse sex-based expression of PTEN and Klotho, two important proteins that are known to negatively regulate the AKT pathway, and inverse sex-dependent levels of mTOR and FoxO3a activity. Taken together, our findings indicate that inverse sex-based regulation may be one of the underlying balancing mechanisms that differ between the sexes and a possible cause of sex-based autophagic and apoptotic responses to triggering situations that can lead to a sex-based predisposition to some neurological diseases.
Highlights
Sex differences are considered predictive factors in the development of several neurological diseases, which are known to coincide with impaired phosphoinositide 3-kinase (PI3K)-AKT pathway activity, an essential signaling cascade involved in the control of several cellular functions such as autophagy and apoptosis
We demonstrate that AKT is not phosphorylated differently between the sexes, nor are autophagic and apoptotic proteins phosphorylated differently by sex, even though we observed that downstream targets such as mTOR and FoxO3a showed different activity levels depending on sex
Since PTEN is essential for brain development, we sought to determine whether this difference is observed at an earlier stage of the animal’s life by PTEN immunostaining of embryonic neuronal cortical cells from both sexes after 7 and 14 days in vitro (DIV)
Summary
Sex differences are considered predictive factors in the development of several neurological diseases, which are known to coincide with impaired phosphoinositide 3-kinase (PI3K)-AKT pathway activity, an essential signaling cascade involved in the control of several cellular functions such as autophagy and apoptosis. Under physiological conditions, we show important sex differences in the underlying balancing mechanisms that lead to similar AKT activity levels and autophagy and apoptosis processes in the two sexes. We demonstrate inverse sex-based expression of PTEN and Klotho, two important proteins that are known to negatively regulate the AKT pathway, and inverse sex-dependent levels of mTOR and FoxO3a activity. Similar to that in PTEN, the reduction in Klotho expression has been linked to the development of some diseases, especially those that are age-related, such as A D13,14 These age-related pathologies are known to have impaired autophagy and apoptosis processes[15], which are regulated, among others, by mTOR and FoxO3a, important downstream targets of the AKT pathway. Our results may contribute to understanding the sex-based differences in autophagy and apoptosis under altered conditions, such as AKT hyperactivation, which can further activate or inhibit basal mTOR and FoxO3a activity levels
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