APOPTOSIS IN NEUROLOGICAL DISEASES

Hassan Mahmoud Hassan Aly;

Abstract


Proliferation and cell death are the two sides of the same coin, rimmed by cellular homeostasis. The regulatory networks controlling the life and death decisions on the cellular level are more complex than we previously thought. The strict regulation of responses to external stimuli maintains tuned the signalling cascades, while unbalance is involved in a number of pathological conditions, ranging from neurodegeneration to neoplastic transformation.
Apoptosis is a well-conserved physiological pathway whose basic tenets appear common to all metazoans. Key components regulate the commitment step and/or participate in effecting cell demise.
Two main trails lead to apoptosis: the death receptor or extrinsic pathway and the mitochondrial or intrinsic pathway. The later is a rapid and strong way to execute the process. Breaches of mitochondria integrity result in the release of proapoptotic factors like cytochrome c. Tough this research area is rapidly developing many issues remain shrouded in uncertainties. The relationship between both mitochondrial membranes is uncertain and controversial. Large pores are involved, though their possible interplay is unclear. Recently the work on mitochondrial cristae remodeling has elucidated a novel checkpoint for apoptosis, which may determine sensitivity to apoptosis in vivo, during adult animal life.
Apoptosis, an essential physiological process that is required for the normal development and maintenance of tissue homeostasis, is mediated by active intrinsic mechanisms, although extrinsic factors can also contribute.
Aerobic metabolism induces the production of reactive oxygen species (ROS), which are able to induce oxidative stress that promotes cellular apoptosis. The mechanisms of ROS-induced modifications in ion transport pathways involves oxidation of sulphydryl groups located in the ion transport proteins, peroxidation of membrane phospholipids, inhibition of membrane-bound regulatory enzymes and modification of the oxidative phosphorylation and ATP levels.
Alterations in the ion transport mechanisms lead to changes in a second messenger system, primary Ca2+ homeostasis. Ca2+ disregulation induces mitochondrial depolarization, which further augments the abnormal electrical activity and disturbs signal transduction, causing cell dysfunction and apoptosis. Control of ROS levels in cells is important, because cellular dysfunction triggered by ROS is a major factor contributing to the development of many diseases. Available evidences show that ROS can induce increases in cytosolic free Ca2+ concentration ([Ca2+]c) by release of the divalent cation from internal stores and impairment of Ca2+ clearance systems. In fact, [Ca2+]c increase is a constant feature of pathological states associated with oxidative stress and apoptosis.
In the central nervous system both neurons and astrocytes play crucial roles. On a cellular level, brain activity involves continuous interactions within complex cellular circuits established between neural cells and glia. Despite it was initially considered that neurons were the major cell type in cerebral function, nowadays astrocytes are considered to contribute to cerebral function too. Astrocytes support normal neuronal activity, including synaptic function, by regulating the extracellular environment with respect to ions and neurotransmitters.
In both cell types Ca2+ signalling plays a pivotal role. Normal Ca2+ homeostasis is required for cell activity, in either in neurons and astrocytes, and must be precisely regulated. On the other hand, mitochondria are the major cellular source for ATP, and are also central for Ca2+ homeostasis. Deregulation of cell cycle has devastating effects on the integrity of cells, and has been closely associated with the development of pathologies which can lead to dysfunction and cell death. Programmed cell death or apoptosis can be activated and/or initiated by different mechanisms involving cell membrane receptor activation, Ca2+ signal impairment, mitochondrial uncoupling or oxidative stress, and involves in its majority, caspase-mediated cleavage cascade.
An alteration of normal neuronal/glial physiology and apoptotic processes could represent the basis of neurodegenerative processes. In this chapter we will pay attention on to the recent findings in neuronal-astrocyte connection and its relationship to apoptosis.
Acute neuronal injury models provide an interesting platform for an


Other data

Title APOPTOSIS IN NEUROLOGICAL DISEASES
Other Titles موت الخليه المبرمج فى الأمراض العصبية
Authors Hassan Mahmoud Hassan Aly
Issue Date 2014

Attached Files

File SizeFormat
g6375.pdf199.91 kBAdobe PDFView/Open
Recommend this item

Similar Items from Core Recommender Database

Google ScholarTM

Check



Items in Ain Shams Scholar are protected by copyright, with all rights reserved, unless otherwise indicated.