Trends in Neurosciences
OpinionActivation of cell-cycle-associated proteins in neuronal death: a mandatory or dispensable path?
Section snippets
Relationship between expression of cell-cycle proteins and neuronal apoptosis in in vitro models of trophic deprivation
The study of cell-cycle proteins in neuronal apoptosis increased following the observation that cyclin D1 is induced early in cultured sympathetic neurons or in neuronally differentiated PC12 cells that have been deprived of nerve-growth factor (NGF) 3. In proliferating cells, cyclin D1 is expressed in the mid G1 phase and forms an active complex with the cyclin-dependent protein kinase 4/6 (CDK4/6), which phosphorylates the retinoblastoma (RB) protein. Activation of CDK4/6 appears to be
Cell-cycle activation in response to DNA damage in neurons
In proliferating cells, DNA damage induces and/or activates specific surveillance factors that cause cell-cycle arrest and promote DNA repair. If the damage is too extensive to be repaired, the same factors then trigger apoptotic death. This function is accomplished by the tumor-suppressing factor p53, and perhaps its cognates p63 and p73. DNA strand breaks signal to p53 mainly via phosphorylation of its transactivation domain, a process leading to an increase in stability and transcriptional
Expression of cell-cycle proteins and excitotoxic neurodegeneration
Induction of cell-cycle proteins has been studied in in vivo models of excitotoxic degeneration, i.e. focal cerebral ischemia and systemic injection of kainic acid. Focal ischemia results in an increased expression of p53 in damaged neurons within the cerebral cortex and corpus striatum 22, and mice lacking p53 are more resistant to ischemic damage 23. Interestingly, McGahan et al. 24 showed that p53 expression is long-lasting only in neurons that are vulnerable to ischemic damage. Ischemic
Cell-cycle activation in response to β-amyloid peptide
Cell-cycle markers, including CDK1, CDK4, cyclins B, D and E, Ki-67, p16ink and p21kip/waf are expressed in neurons from AD brain 39., 40., 41., 42., 43., 44., 45.. The reappearance of mitotic proteins should not be interpreted as a by-product of apoptotic degeneration because it is not necessarily associated with the end stages of neuropathology. Because neurons of the AD brain express either cyclin E or -B, but never cyclin A, Nagy et al. 45 suggested that the cell cycle is activated but not
When and how cell-cycle activation becomes mandatory for neuronal death
One of the emerging concepts is that the contribution of cell-cycle related factors to neuronal apoptosis is not unequivocal. There are situations in which cell-cycle signaling is not required for death, for example in sympathetic neurons subjected to an intense oxidative stress 7. However, this does not imply that a cell cycle is not activated under these conditions, but only that neurons die regardless of it. In many other cases, the cell death pathway proceeds along the reactivation of the
Concluding remarks
In conclusion, in vitro data suggest that cell-cycle activation in neurons becomes an obligatory component of the cell death pathway when combined with other mechanisms that are not sufficient to reach the threshold for cell death. According to this hypothesis, the re-expression of cell-cycle proteins observed in pathological brains is not interpreted as an epiphenomenon, but rather as an essential component of the death program. This hypothesis must be validated by solid in vivo data, which is
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2018, NeuroscienceCitation Excerpt :Unfortunately, attempts at cell division by a mature neuron are considered fatal (Herrup and Busser, 1995) making the identification of the factor/s that cause neurons to enter the cell cycle crucial. The DNA damage theory posits that ineffective repair of DNA damage results in faulty gene expression, cell dysfunction and eventual cell death via reentry into the cell cycle (Copani et al., 2001) resulting in reduced rates of aneuploidy observed at end stage disease (Arendt et al., 2010). The mechanisms that cause DNA damage are manifold and include oxidative stress, abnormal protein production and deposition, and hormone changes to name a few (Kruman et al., 2004; Kuan et al., 2004; Rashidian et al., 2007; Atwood and Bowen, 2015).
Excitotoxicity
2018, Comprehensive Toxicology: Third Edition