Ros

Cyclin-Cdk induction

Cyclin-Cdk induction

Induction of proapoptotic factors (e.g. Cdc2 phosphorylation of BA "

Cell cycle-independent induction of proapoptotic factors

Fig. 2. ROS-induced apoptosis may be promoted by multiple pathways: Oxidative stress-induced neuronal apoptosis may be cell cycle-dependent or independent. Increased reactive oxygen species (ROS) may result in reactivation of cell cycle function and unscheduled cell cycle reentry. Uncoordinated cell cycle progression results in uncoupled DNA synthesis and mitosis, invoking mitotic catastrophe and death. Alternatively, because Cdks can have dual roles in promoting cell cycle progression or apoptosis, their activation in a postmitotic neuron by ROS may result in death that is independent of cell cycle reentry. Finally, death induced by oxidative stress may be independent of both cell cycle reentry and Cdk function. Instead, increased ROS induces the activation of proapop-totic factors leading to apoptosis. Which or how many of these pathways are induced may depend on the strength of the stimulus.

The relationship between cell cycle processes and apoptosis induced by oxidative stress is even more poorly understood. This may primarily be due to the involvement of multiple pathways, both cell cycle-dependent and independent, that promote death in neurons during oxidative stress (Fig. 2). Indeed, the determining factor of which or how many pathways are induced may be dependent on the level and duration of oxidative stress. Lower levels of ROS in a postmitotic neuron may induce cell cycle protein expression leading to death, whereas high or sustained ROS may induce apoptosis via a different pathway, or multiple pathways simultaneously. As discussed, this idea would be consistent with why cell cycle inhibitors do not prevent apoptosis induced by strong oxidative stress, and why cell cycle protein activation is not seen in some oxidative stress-induced death paradigms (14,128). It would also have important consequences with respect to neuroprotective therapies. A specific strategy targeting one apoptotic pathway, may just delay death until a different pathway is utilized, suggesting effective strategies will be ones that target several apoptotic pathways simultaneously. On the other hand, inhibiting the death of an irreparably damaged neuron that has been exposed to high levels of oxidative stress may not be particularly advantageous. Accordingly, a therapy protecting moderately stressed neurons with repairable damage may be more desirable. In either case, understanding the roles and interplay of potential pathways leading to cell death is vital for understanding the role of ROS in neurodegenerative disorders.

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