Oxidative Stress

This week, in the Journal of Neurochemistry, Choi and colleagues report protection against oxidative stress (OS)-induced cell death by a novel gene, Oxi-alpha, which is expressed specifically in DA neurons in the substantia nigra.  In SN4741 and SH-S75Y cells, its expression decreases following OS. Furthermore, knockdown using siRNA against Oxi-alpha makes cells more susceptible to OS-induced toxicity, while over-expression of Oxi-alpha is protective (Choi et al., 2009).   

Because OS typically induces autophagy, a degradative process shown to be involved in several neurodegenerative disorders including PD, the authors wanted to assess whether Oxi-a exerted its protective effects by modulating the autophagic pathway (Byun et al., 2009; Zhang et al., 2009, Martinez-Vicente and Cuervo, 2007).  They show that rapamycin, which induces autophagy by blocking the kinase mammalian target of rapamycin (mTOR), increased OS-induced cell death, while 3-methyladenine (3MA), an autophagy blocker, was protective. Oxi-alpha-mediated protection against OS-induced cell death seems to be mediated by inhibition of autophagic vacuole (AV) formation as Oxi-alpha over-expression prevented the accumulation of AVs following rapamycin treatment, OS, and amino acid deprivation, which also activates autophagy. 

AV formation is controlled by mTOR, which suppresses autophagy under normal conditions.  To assess whether Oxi-alpha is involved in mTOR signaling, the authors quantified the levels of phospho-mTOR and found that over-expression of Oxi-alpha increased phospho-mTOR, while Oxi-alpha knockdown resulted in a decrease in phospho-mTOR and phospho-p70 S6 kinase, a target of mTOR. The authors argue that Oxi-alpha is protective against OS by maintaining mTOR active, thus suppressing autophagy and autophagic cell death. 

Even though the paper sheds light on how Oxi-alpha expression and activity may be involved in neuroprotection under pathological conditions, the molecular mechanism downstream of mTOR by which it exerts protection needs to be elucidated. Confirming that cell death is not apoptotic in nature will also be important. Results by other researchers show that 3-MA treatment following exposure to hydrogen peroxide results in an increase in apoptosis (Zhang et al., 2009). It is possible that the length of exposure to OS may account for these differences. Understanding by what mechanism cell death occurs will be important for developing efficient treatments. Furthermore, it will be interesting to see whether modulating Oxi-alpha levels and activity in animals is protective against MPTP- or 6OHDA-induced toxicity.