Classically, the cell cycle is regarded as the process leading to cellular proliferation. However, increasing evidence over the last decade supports the notion that neuronal cell cycle re-entry results in post-mitotic death. A mature neuron that re-enters the cell cycle can neither advance to a new G0 quiescent state nor revert to its earlier G0 state. This presents a critical dilemma to the neuron from which death may be an unavoidable but necessary outcome for adult neurons attempting to complete the cell cycle. In contrast, tumor cells that undergo aberrant cell cycle re-entry divide and can survive. Thus, cell cycle inhibition strategies are of interest in cancer treatment but may also represent an important means of protecting neurons. In this review, we put forth the concept of the "expanded cell cycle" and summarize the cell cycle proteins, signal transduction events and mitogenic molecules that can drive a neuron into the cell cycle in various CNS diseases. We also discuss the pharmacological approaches that interfere with the mitogenic pathways and prevent mature neurons from attempting cell cycle re-entry, protecting them from cell death. Lastly, future attempts at blocking the cell cycle to rescue mature neurons from injury should be designed so as to not block normal neurogenesis.
Published by Elsevier Inc.