User talk:Dskvm

Apoptosis (derived from the Greek word meaning “falling off”) is a form of programmed cell death to maintain a constant cell number and ensure optimum functioning.The cell undergoes several morphological changes while dying via apoptosis: the cell shrinks, the cytoskeleton collapses, chromatin condenses, the surface often blebs and phosphotidylserine located on the inner plasma membrane flips to the outer membrane and this helps neighbouring cells or macrophages rapidly engulf them without spilling their contents. Neurons are post-mitotic and generally survive for the entire lifetime of the organism.This enduring nature of neurons is essential for the functioning of the neuronal cells.Neuronal apoptosis thereby is the cause of several neurological disorders such as Alzheimer’s, Parkinson’s and Huntington’s disease.

Death Signals

Apoptosis can be initiated by several environmental and genetic factors. Death. Like in any other cell, an increase in metabolic or oxidative stress can trigger the apoptotic cascade in neurons(9,10). In neurons, the lack of neurotrophic support factor can also prompt the programmed cell death reactions during the development of the neural system(2,3,4). The over-activation of the glutamate receptor is also a neuron-specific triggger which acts by increasing the calcium flux with the cell(5,6 ). It is to be noted, in-spite the variety of triggers that elicit an apoptotic response in a cell, the subsequent series of reactions that leads to cell death is highly conserved.

Apoptosis Cascade

A death signal activates an intracellular cascade of events. This involves an immediate increase in levels of of oxyradicals and Ca+2 ions which acts as second messengers for the cascade. This subsequently enhances the translation of par-4 mRNA which in-turn increases the levels of Bcl proteins such as Bax and Bad. These increased expression of these two proteins marks the effector phase as they act on the mitochondrial membrane forming PTPs ensuing the release of cytochrome-C into the cytosol. Cytochrome-C binds to caspase-9 activating it which successively activates caspase-3. The activation of caspase-3 begins the degradation phase of apoptosis in which various caspases cleaves various enzymes, cytoskeleton and various ion-channel metabolites.

Regulation of Apoptosis

The decision to live or die is crucial for a cell especially for a neuron because of its inability to divide. Therefore there are several prominent pathways that curb the apoptosis and each targets the pathway at multiple levels(3).These pathways involves a set of proteins known as anti-apoptotic proteins which as often opposing functions to those proteins involved in the apoptotic pathways. For example, Bcl-2 and Bcl-x stabilizes the mitochondrial function and reduces the oxidative stress counteracts the functions of the Bax and Bad molecules. Inhibitor of Apoptosis proteins(IAPs) as the name suggest inhibits apoptosis by binding to caspase proteins. XIAP is one of the well-characterized proteins which is known to bind with caspase-9, caspase-3 and caspase-7. Apart from this, there are various other enzymes inclusive of calcium binding enzymes for maintaining homeostasis and anti-oxidant enzymes for suppressing the oxidative stress. The death signals increases the proapoptotic factors relative to anti-apoptotic factors and thus intiating cell death.

Synaptic pathways and signals

Primary signalling elements of apoptotic cascade are highly concentrated in the synapses between the neurons. The glutamate receptors are present in the post-synaptic pathways(105) and under a nutrient deprived condition they get activated promoting apoptosis involving an increase in Ca+2 ions. Also, the R-receptors for neurotrophic factors are present in the axons(106). Upon activation of these receptors there is a considerable increase in anti-apoptotic proteins such as Bcl-2, Bcl-x and IAPs. Also, anti-apoptotic proteins can play in modulating the synaptic plasticity of the neural network as seen in NF-Kb. Therefore, an alteration in the functioning of the neurites can create an imbalance between proapoptotic-antiapoptotic levels and vice-versa.