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 edit
Apoptosis can be initiated by several environmental and genetic factors. Like in any other cell, an increase in metabolic or oxidative stress can trigger the apoptotic cascade in neurons[1][2]. Also, the lack of neurotrophic support factor can promote the apoptosis cascade during the development of the neural system[3][4][5]. The over-activation of the glutamate receptor is also a neuron-specific trigger which acts by increasing the calcium influx[6][7]. 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 lead to cell death are highly conserved.
Apoptosis Cascade edit
A death signal initiates an intracellular cascade of events. This involves an immediate increase in levels of of oxyradicals[1][2] and Ca+2[6][7] ions which acts as second messengers for the cascade. This subsequently enhances the translation of par-4 mRNA[8][9] which in-turn increases the levels of proapoptotic proteins of the Bcl-2 family such as Bax and Bad[10]. The increased expression of these two proteins marks the effector phase as they act on the mitochondrial membrane forming mitochondrial permeability transition pores (MPTPs) 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 cleave various enzymes, cytoskeleton and various ion-channel metabolites.
Regulation of Apoptosis edit
The decision to live or die is crucial for a cell and 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 different levels[4](3). These pathways involves a set of proteins known as anti-apoptotic proteins which often have opposing functions to those proteins involved in the apoptotic pathways. For example, Bcl-2 and Bcl-xL stabilize the mitochondria and reduce the oxidative stress thereby counteracting the effects of the Bax and Bad molecules. Inhibitor of apoptosis proteins(IAPs), as the name suggests, inhibit 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. In a living, healthy cell there exists a delicate balance between the pro and anti apoptotic factors. The death signals increase the proapoptotic factors relative to anti-apoptotic factors and thus initiate cell death.
Synaptic pathways and signals edit
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[11] and get activated under a nutrient deprived condition promoting apoptosis involving an increase in Ca+2 ions. Also, the R-receptors for neurotrophic factors are present in the axons[12]. Upon activation of these receptors there is a considerable increase in anti-apoptotic proteins such as Bcl-2, Bcl-xL and IAPs. Also, anti-apoptotic proteins can play a role 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.
References edit
- ^ a b Sastry, P. S. & Rao, K. S. Apoptosis and the nervous system. J. Neurochem. 74, 1–20 (2000).[1]
- ^ a b Mattson, M. P. Modification of ion homeostasis by lipid peroxidation: roles in neuronal degeneration and adaptive plasticity. Trends Neurosci. 21, 53–57 (1998)[2] Cite error: The named reference "Mattson" was defined multiple times with different content (see the help page).
- ^ Oppenheim, R. W. Cell death during development of the nervous system. Annu. Rev. Neurosci. 14, 453–501(1991).[3]
- ^ a b Mattson, M. P. & Lindvall, O. in The Aging Brain Vol. 2 (eds Mattson, M. P. & Geddes, J. W.) 299–345 (JAI Press, Greenwich, Connecticut, 1997).[4]
- ^ McKay, S. E., Purcell, A. L. & Carew, T. J. Regulation of synaptic function by neurotrophic factors in vertebrates and invertebrates: implications for development and learning. Learn. Mem. 6, 193–215 (1999).[5]
- ^ a b Ankarcrona, M. et al. Glutamate-induced neuronal death: a succession of necrosis or apoptosis depending on mitochondrial function. Neuron 15, 961–973 (1995).[6]
- ^ a b Glazner, G. W., Chan, S. L., Lu, C. & Mattson, M. P. Caspase-mediated degradation of AMPA receptor subunits: a mechanism for preventing excitotoxic necrosis and ensuring apoptosis. J. Neurosci. 20, 3641–3649 (2000)[7].
- ^ Guo, Q. et al. Par-4 is a mediator of neuronal degeneration associated with the pathogenesis of Alzheimer's disease. Nature Med. 4, 957–962 (1998).[8]
- ^ Mattson, M. P., Duan, W., Chan, S. L. & Camandola, S. Par-4: an emerging pivotal player in neuronal apoptosis and neurodegenerative disorders. J. Mol. Neurosci. 13,17–30 (1999).[9]
- ^ Pellegrini, M. & Strasser, A. A portrait of the Bcl-2 protein family: life, death, and the whole picture. J. Clin. Immunol. 19, 365–377 (1999).[10]
- ^ Mattson, M. P. & Duan, W. Apoptotic biochemical cascades in synaptic compartments: roles in adaptive plasticity and neurodegenerative disorders. J. Neurosci. Res. 58, 152–166 (1999).
- ^ Ivins, K. J., Bui, E. T. & Cotman, C. W. Beta-amyloid induces local neurite degeneration in cultured hippocampal neurons: evidence for neuritic apoptosis. Neurobiol. Dis. 5, 365–378 (1998).http://www.sciencedirect.com/science/article/pii/S0969996199902681