Neuronal Cell Cycle Regulation Research Articles

Cell Cycle Deficits in Neurodegenerative Disorders: Uncovering Molecular Mechanisms to Drive Innovative Therapeutic Development.

Cell cycle dysregulation has been implicated in the pathogenesis of neurodegenerative disorders. Specialised function obligates neuronal cells to subsist in a quiescent state of cell cycle once differentiated and therefore the circumstances and mechanisms underlying aberrant cell cycle activation in post-mitotic neurons in physiological and disease conditions remains an intriguing area of research. There is a strict requirement of concurrence to cell cycle regulation for neurons to ensure intracellular biochemical conformity as well as interrelationship with other cells within neural tissues. This review deliberates on various mechanisms underlying cell cycle regulation in neuronal cells and underscores potential implications of their non-compliance in neural pathology. Recent research suggests that successful duplication of genetic material without subsequent induction of mitosis induces inherent molecular flaws that eventually assert as apoptotic changes. The consequences of anomalous cell cycle activation and subsequent apoptosis are demonstrated by the increased presence of molecular stress response and apoptotic markers. This review delineates cell cycle events under normal physiological conditions and deficits amalgamated by alterations in protein levels and signalling pathways associated with cell-division are analysed. Cell cycle regulators essentially, cyclins, CDKs, cip/kip family of inhibitors, caspases, bax and p53 have been identified to be involved in impaired cell cycle regulation and associated with neural pathology. The pharmacological modulators of cell cycle that are shown to impart protection in various animal models of neurological deficits are summarised. Greater understanding of the molecular mechanisms that are indispensable to cell cycle regulation in neurons in health and disease conditions will facilitate targeted drug development for neuroprotection.

Neuronal Cell Cycle Regulation of Cdk5 in Alzheimer's Disease

Neuronal cell cycle dysregulation is closely related with the neuronal death in Alzheimer’s disease (AD), but the detailed mechanism linking the two processes is unclear. Cyclin-dependent kinase 5 (Cdk5) is described as an atypical Cdk, which has been shown to have no cell cycle promoting activity. Yet while Cdk5 may not promote the cycle, we have found that Cdk5 may play a role in maintaining the quiescent stage of post-mitotic neuron. In this chapter, we review recent findings concerning the cell cycle suppression activity of Cdk5, and relate this function to the initiation and progression of neurodegenerative diseases, in particular AD. Our data suggest that nuclear Cdk5 can block the cell cycle. When the post-mitotic neuron is subjected to β-amyloid stress, Cdk5 is translocated from nucleus to cytoplasm. Deprived of its nuclear Cdk5, the post-mitotic neuron will re-enter into cell cycle, ultimately leading the cycling neuron to die rather than divide. Our work has identified the molecular basis of the cell cycle suppression effect of Cdk5. Taken together, our data reveal that Cdk5 does indeed regulate cell cycle activity. These finding may provide new pharmacotherapeutic approach to treating brain disorders such as AD.

Pin1 inhibition activates cyclin D and produces neurodegenerative pathology

Abnormal cell cycle events are increasingly becoming important attributes of neurodegenerative pathology. Pin1 is a crucial target of neurodegeneration in relation to its functions regarding these abnormal cell cycle events in neurons. Pin1 is majorly involved in many aspects of cell cycle regulation and it has also been suggested to have a neuroprotective function against neurodegenerative pathologies. Oxidative dysregulation of Pin1 affects not only normal tau regulation, eventually causing tangle formation, but also cell cycle regulation in neurons. Presence of cell cycle proteins has been shown in many neurodegenerative diseases. Importantly, many of these proteins have physical interactions with Pin1. Hence, understanding Pin1's role in abnormal cell cycle re-entry is critical in terms of finding new approaches for the future therapeutic options treating neurodegenerative pathologies. Here, we show that inhibition of Pin1 by its selective inhibitor juglone leads to up-regulation of cyclinD1, phospho-tau, and caspase 3, producing apoptosis in cultured rat hippocampal neurons. We also observed axonal retraction with a change in sub-cellular localizations of cyclins. Therefore, Pin1 dysregulation, in relation to its role in cell cycle regulation in neurons, may have profound effects in the progression of neurodegenerative pathology, making it a possible crucial target behind many neurodegenerative diseases.

Ca 2+/calmodulin-dependent modulation of cell cycle elements pRb and p27 kip1 involved in the enhanced proliferation of lymphoblasts from patients with Alzheimer dementia

Failure of cell cycle regulation in neurons might be critically involved in the process of neurodegeneration in Alzheimer’s disease (AD). We present here evidence to support the hypothesis that cell cycle alterations occur in cells other than neurons in AD sufferers. Lymphocytes from AD patients immortalized with Epstein-Barr virus showed an enhanced rate of proliferation and increased phosphorylation of the retinoblastoma protein (pRb) and other members of the family of pocket proteins compared with cell lines derived from normal age-matched controls. The calmodulin antagonist calmidazolium, as well as W-7 and W-13, abrogated the enhanced activity of AD cells without altering the normal basal rate of proliferation. The effect of calmidazolium was accompanied by partially dephosphorylation of pRb. No changes were found in the expression levels of the G1 cyclin/Cdks complexes. However, lymphoblasts derived from AD patients showed reduced levels of the Cdk inhibitor p27 kip1, which were restored after anti-calmodulin treatment of the cultures. These observations suggest that in AD cells the enhanced rates of cell proliferation and phosphorylation of pRb and the intracellular content of p27 kip1 may be interrelated events controlled by a mechanism dependent on the Ca 2+/calmodulin signaling pathway. The distinct functional features of lymphoblastoid cells from AD patients offer an invaluable, noninvasive tool to investigate the etiopathogenesis, and eventually, for the early diagnosis and prognosis of this devastating disease.