Schematic representation of the eukaryotic cell cycle – Cyclin A-CDK2 phosphorylates a variety of substrates throughout S phase, allowing DNA replication. When S phase completed, DNA replication ceases and then cells enter the G2 phase of the cell cycle. Then CDK2 is replaced by CDK1 that linked with cyclin A and control the phosphorylation of G2 and M phases specific proteins together with cyclin B-CDK1, that appears in late G2 phase and triggers the G2/M transition. Cyclin A is ruined and the cycle is reorganized, re-establishing the condition for mitogenic cues to provoke D-type cyclins for the next cell cycle. In M phase, cells physically divide and originate two separate daughter cells Source: Currais et al. (2009). 

Contexts in source publication

Context 1

... rise to new neurons (Jessberger et al., 2009). Cdk5 is involved in the movement of newly born neurons of the granule cell layer (GCL). Cdk5 also takes part in exact targeting of dendrites from newly born granule cells (GC) into the molecular layer (ML) of the dentate gyrus (DG). Throughout life the newly born neurons are added to dentate circuitry, with the hippocampal neural progenitor cells NPCs (Albert et al., 2009). Permanent production of new neurons is vital for brain function. The newly formed cells play two distinct roles, firstly the new neurons take part in maintenance of tissue in the olfactory system and secondly they are essential for the development of memory like associative and spatial memory in the hippocampus (Imayoshi et al., 2008). The role of cdk5 in guiding new neurons to their proper place has been discovered, which has increased the understanding of adult neurogenesis, improved understanding of its involvement in cognitive function and brightened the expectations for brain cell therapy (Albert et al., 2009). Also, scarcity in hippocampal neurogenesis has been related with a number of neurological diseases, including AD, epilepsy, major depressions (Albert et al., 2009) and neuropsychiatric illnesses, such as addiction (Hawasli et al., 2009). The abnormal insoluble fibrous proteins are deposited with different proportion inside brain. The localization of fibrous insoluble proteins inside the brain is a characteristic features of several disorders, including AD, PD and Lewy body dementia (LBD) (Mierczak et al., 2011). AD is a progressive and slowly occurring disorder which degrades the central nervous system (CNS) character- rized by impairment of cognitive function and appearance of neuropathological characters, including amyloid plaques. These amyloid plaques are composed of Aβ, NFT and linked to cholinergic neuronal loss in selective brain parts (Nakdooka et al., 2010). The major component of amyloid plaques is Aβ, which is considered as a key molecule in AD pathogenesis (Uetsuki et al., 1999). Inflammation is the third significant pathological feature in AD, apart from NFTs and amyloid plaques (Muyllaert et al., 2008). The oxidative stress hypothesis of AD pathogenesis is based on Aβ peptide, which initiates oxidative stress in both in vitro and in vivo studies (Sultana et al., 2009). In a normal physiological pathway, amyloid precursor protein (APP) is converted and secreted as amyloid precursor protein (sAPP) which is responsible for the function of growth factor. However, in amyloidogenic pathway, the mutation in APP and presenilin increases the formation of Aβ40 and Aβ42 ( Chen et al., 2012). They form aggregates due to mutation in lipid transport protein, that is ApolipoproteinE4 (ApoE4) gene. The production of Aβ40 usually occurs in small amounts, while Aβ42 is produced in higher amounts as a result of the genetic genetic mutations mentioned above (Mann et al., 2011). Both Aβ40 and Aβ42 proteins aggregate to form amyloid plaques, but Aβ42 shows a stronger affinity than Aβ40 to do so, and appears to be the main cause in amyloid formation (Rang et al., 2007) . The Aβ40 and Aβ 42 are formed by proteolytic cleavage of a much larger (770 amino acid) APP (Figure 1). The Aβ accumulation is the cause of neurodegeneration, but whether the damage is done by soluble Aβ monomers or by amyloid plaques remains uncertain. Appearance of Alzheimer mutations in transgenic animal results in development of plaque and neurodegeneration (Rang et al., 2007). The aggregation of Aβ40 and Aβ42 also activate the kinase that causes the phosphorylation of Tau protein (Figure 1). Tau, a usual part of neurons, is intracellular microtubules binding protein (Chatterjee et al., 2009). In AD and other tauopathies, phosphorylated tau protein is deposited within the cell as paired helical filaments which have typical microscopic features. After the destruction of cells, these filaments are combined as extracellular neurofibrillary tangles (Crews and Masliah, 2010). It may be possible, but not proven, that the phosphorylation of tau protein is improved by th e presence of Aβ plaques. However, it is not sure that hyperphosphorylation and intracellular deposition of tau harm the cells. Although it is known that tau phosphorylation damage fast axonal transport, which depends on microtubules (Rang et al., 2007). Nineteen specific amino acid sequences throughout its 441 amino acids have been recognized in tau, for its phosphor- rylation, (Augustinack et al., 2001) associated with paired helical filaments. CDK5 has been considered a main tau kinase that takes part in tau pathology (Alvarez et al., 1999), the other most important tau kinases that takes part in tau pathologies are GSK3α, GSK3β and Casein kinase 1α (CK1α) (Martin et al., 2013). There are four main successive phases in a eukaryotic cell cycle: G1 phase (first gap), S phase (DNA synthesis), G2 phase (second gap) and M phase (mitosis) (Figure 2). Change between the various phases and consecutive progression through the mitotic cycle is modulated by a group of protein kinases whose activity is essential to this process. The cyclin-dependent kinase (CDKs) requires the binding of their activating partner cyclins; whose levels of appearance vary throughout the cycle. Two important checkpoints (G1/S and G2/M) direct CDKs activity and manage the order and timing of cell-cycle transitions to ensure that DNA replication and chromosome segre- gation are finished correctly before allowing additional progress throughout the cycle (Currais et al., 2009). Neurons are born throughout the entire life in limited brain areas of mammals, including humans (Jessberger et al., 2009). After the formation of a neuron, it loses the capability for cell division and differentiation, ...

Context 2

... to the plasticity of the basic wiring model that defines a neuronal system. The conservation of this pattern is essential for the overall generation and storage of memories, as well as for gaining of other ad-vanced brain skills. Some researcher have reported that neuronal apoptosis is accompanied by the appearance of cell cycle markers. Mainly, cyclins and cyclin-dependent kinases (CDKs) take part in cell cycle machinery ( Figure 2). The cell cycle may be up regulated after exposure to severe conditions, like oxidative stress and trophic factor deficiency (Currais et al., 2009; Zhang et al., 2008). The 9 small serine/threonine kinases take part in the formation of Cdk family. They are numbered based on their discovery, that is from Cdk1 to Cdk9. The biological functions of Cdks are many which ranges from mitosis to the regulation of cellular processes (Cardone et al., 2010). 2010). Cdks are involved in functions like differentiation, senescence and programmed cell death, via modification of gene transcription. In proliferating cells, the tumor production is mainly linked with Cdk dysregulation (Zafonte et al., 2000). The disappearance or inhibition of neuronal precursors takes place with terminal differentiation (Okano et al., 1993). Normally, in order to be activated, Cdks require connecting with regulatory subunits named cyclins. Although specific Cdks are linked to various phases of the cell cycle, sometimes their activities overlap, depending on the association with different cyclins. Cdk action can also be regulated by two other distinct mechanisms. A set of phosphorylation and dephosphorylation actions make ready Cdks for activation by regulatory subunits, as in the case of the Cdk4/cyclin D1 complex, which are activated only after phosphorylation by the Cdk-activating kinase (CAK). Additionally, a family of Cdk-inhibitory subunits (CKIs) can bind to it and inactivate the Cdk – cyclin complex (Lopes and Agostinho, ...