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

Abstract

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.

Dexmedetomidine protects SH‐SY5Y cells against MPP+‐induced declining of mitochondrial membrane potential and cell cycle deficits

“…After neurons were exposed to oxidative stress, the expression of cell cycle markers was up‐regulated(Schwartz et al., 2007). When the neuron cell cycle reactivation, it may cause cell apoptosis (Joseph et al., 2020). (Frade & Ovejero‐Benito, 2015)Aberrant activation of cell cycle and abnormal expression of mitotic related proteins in the substantia nigra (SN) were found in PD autopsy tissues(Jordan‐Sciutto et al., 2003) and mice model (Smith et al., 2003).…”

“…During S phase, the cyclin A/Cdk1 complex activates late replication origins. Finally, G2/M transition is regulated by the formation of the Cdk1/cyclin B complex, which helps cells enter the M phase (Joseph et al, 2020). The western blotting results showed that MPP + increased the expression of cyclinD1, CyclinE1, CDK2 and cyclinA2 in SH-SY5Y cells.…”

Elucidating the Multi-Targeted Role of Nutraceuticals: A Complementary Therapy to Starve Neurodegenerative Diseases

“…Different mechanisms have been implicated in the progression and pathogenesis of NDs, including OS, neuroinflammation, apoptosis, excitotoxicity, and mitochondrial dysfunction [ 43 , 44 , 45 , 46 , 47 ] ( Figure 1 ).…”

“…Extrinsic and intrinsic pathways consist of death receptor activation upon ligand binding and production of pro-apoptotic factors in cytosol, respectively. Subsequently, the intrinsic pathway triggers caspase-independent apoptosis or caspase-dependent apoptosis [ 46 , 48 ]. Characterized by chromatin condensation, cell shrinkage, membrane cell death, and DNA fragmentation, neuronal apoptosis is the neuropathological hallmark of NDs.…”

Breast cancer type 1 and neurodegeneration: consequences of deficient DNA repair

“…Although neurons are post-mitotic, cell cycle re-entry can occur following defective DNA repair. In fact, re-initiation and dysregulation of the cell cycle is a recognized feature of neurodegenerative disorders, 119 , 120 where dysregulation can occur from various stressors, such as excitotoxicity, oxidative stress and DNA damage. 121 This process can induce senescence or apoptosis depending on the extent of cell cycle progression and the amount of DNA damage present.…”