Cell division in the CNS: protective response or lethal event in post-mitotic neurons?

Abstract

Cell cycle events have been documented to be associated with several human neurodegenerative diseases. This review focuses on two diseases--Alzheimer's disease and ataxia telangiectasia--as well as their mouse models. Cell cycle studies have shown that ectopic expression of cell cycle markers is spatially and regional correlated well with neuronal cell death in both disease conditions. Further evidence of ectopic cell cycling is found in both human diseases and in its mouse models. These findings suggest that loss of cell cycle control represents a common pathological root of disease, which underlies the defects in the affected brain tissues in both human and mouse. Loss of cell cycle control is a unifying hypothesis for inducing neuronal death in CNS. In the disease models we have examined, cell cycle markers appear before the more well-recognized pathological changes and thus could serve as early stress markers--outcome measures for preclinical trials of potential disease therapies. As a marker these events could serve as a new criterion in human pathological diagnosis. The evidence to date is compatible with the requirement for a second "hit" for a neuron to progress cell cycle initiation and DNA replication to death. If this were true, any intervention of blocking 'second' processes might prevent or slow the neuronal cell death in the process of disease. What is not known is whether, in an adult neuron, the cell cycle event is part of the pathology or rather a desperate attempt of a neuron under stress to protect itself.

Figure 1

Cell cycle events associated with degenerating neuronal cells in AD & A-T. A. A hippocampual neuron from an AD patient specimen shows cyclin B positive immunostaining (from Yang et al., 2003). B. PCNA expressed in the cerebellar Purkinje cells of diagnosed A-T patient. C. In cortical neurons of the transgenic R1.40 mouse, the cell cycle marker, cyclin A, is re-expressed (arrows). D. PCNA is expressed in the cerebellar Purkinje cells of atm-deficient mouse. E. FISH analysis shows four bright hybridization signals from a unique locus in the mouse genome, indicating that DNA replication has occurred in the hippocampal neuron of transgenic R1.40 mouse (from Yang et al., 2006). F. DNA replication also can be found in the Purkinje cells of the atm-deficient mouse (from Yang et al., 2005).

Figure 2

Cell cycle associated cell death in neuronal cells. A. During the neurogenic period cells divide rapidly in the region of the ventricular zone. B. After leaving ventricular zone, neurons become permanently post-mitotic and begin their migration to their final adult location. C. During and after migration is complete the neurons completes its morphological and biochemical differentiation program. D. Before they have reached a certain state, any interruption of cell cycle control results in the neuron re-entering a cell cycle followed by death within hours. E. In a mature neuron, any mitotic stress or stimulus that induces neuron reenter into a cell cycle will lead to a state which is permissive, but not sufficient to lead to neuronal death. F. We hypothesize that a second “hit” (oxidative, inflammation and DNA breaks) is needed to push the process of cell death in the adult neuron.