Essay: Cell death in health and disease

Introduction
Since the 19th century cell death has been scrutinised and appreciated but until the 20th century no experimental investigation had taken place. [1] It was later suggested that programmed cell death (PCD) has been a vital mechanism in the survival of multicellular organisms. Cell death is an ongoing process in the human body before and after birth. In the body both physiological (Apoptosis and Autophagy) and pathological (Necrosis) processes occur to maintain homeostasis. It plays an important role in protecting the body from small infections to diseases such as cancer. Cell death is often described as a double edged sword in the sense that it can be both beneficial and harmful. Uncontrolled cell death has been an explanation for many Neurodegenerative diseases such as Alzheimer’s and Parkinson’s. In contrast inhibition of cell death has often been the cause of developing cancer. This essay will outline and examine the mechanisms of the different cell deaths which occur in the body before and after birth and discuss the pathway of diseases caused by both excessive and insufficient cell death.
Cell death before birth
PCD is an important mechanism in the formation of limbs during the embryonic development period. Apoptosis is responsible for the death of extra cells which are produced to ensure that there is no shortage during organ and limb development. The cells which make up the extra tissues are broken down in the interdigital regions. It is controlled by signaling proteins. Inhibition of transferring growth factors could lead to anomalies in the limb development and is the explanation for conditions referred to as syndactyly [2]. There are various types of syndactyly conditions. Cutaneous syndactyly results as a failure of complete PCD (see figure 1a). The limb defect emerges from the lack of apoptosis and formation of extra fingers or toes during embryogenesis. On the other hand osseous syndactyly is a condition where there is excessive cell death resulting in failure of the digital rays to separate. Consequently this leads to the formation of joined finger or toes (see figure 1b) [2]. PCD is important in the development of limbs in embryos but it is essential that apoptosis is regulated and controlled to benefit the body rather than contributing to disease. This process continues in the body after birth.
Pathological Cell Death
Necrosis is a pathological cell death which follows a different mechanism from the programmed cell death (these have evolved to benefit the body). Therefore it is described as a passive and nongenetically programed cell death.3 This death mechanism is distinct from the PCD in several ways; from the structural features to the timing of the pathways. The degenerated cells in Necrotic deaths are swollen an enlarged in comparison to the normal PCD, and occurs over a period of several hours.4 There are many different conditions which can initiate cell death by necrosis. One of the triggers is the change in the permeability of the ion channels in the cell surface membrane. This leads to the activation of lysosome rupture thus resulting in DNA fragmentation and consequently cell death. It has been suggested that necrotic cell death is a major component in the damage to the nervous system during neurodegeneration.5 Necrosis is a form of cell death that contributes to disease in the human body unlike apoptosis (programmed cell death).
Physiological Programmed Cell Death (PCD)
One of the most understood and common form of programmed cell death (PCD) is by Apoptosis. Apoptosis is an evolutionary mechanism for the selectively removal of damaged, ageing and unnecessary cells in the body therefore this system of PCD has many different mechanisms. This essay will look at the mitochondrial mediated pathway as the mitochondria is vital to the survival of multicellular organisms. The active central role of mitochondria in PCD had not been evident until the mid- 1990s.1 They are thought to be the primary organelles in regulating the apoptotic pathways by responding to stress stimuli including different forms of radiation, environmental factors, genes and DNA damage. These signals to the mitochondria are interpreted by multiple cytosolic or intraorganellar molecules which eventually give rise to adjustments in the outer mitochondrial membrane.1 One of these adjustment could be change in the permeability of the membrane to proteins which would otherwise be present between the inner, and the outer mitochondrial membrane. These proteins escape the mitochondria and initiate apoptosis by activating caspase-3. 1 This is described as the intrinsic pathway (see figure2). The mitochondria can also follow the extrinsic pathway which is initiated by death ligands (see figure2). Here death ligands generate signals which can either directly engage the mitochondria through a series of events activating the effector (caspase-3) or promote the cleavage of non-caspase substrates stimulating changes in the outer mitochondrial membrane. This causes the release of apoptogenic factors. 1 If apoptosis is not possible for the cell to carry out it will initiate type II PCD (Autophagy) as an alternative .1
Autophagy is induced by stress situations. In this cell death pathway autophagosomes deliver intercellular proteins and organelles to lysosomes for destruction.3 This is a process where the cell recycles its components through self-consumptions. One of the common stress stimuli which can induce autophagy is by oxidative stress which results in myocardial infarction. Here autophagy is not a contributor to ischaemic cardiac diseases but is an adaptive response to ischaemic stress showing its role in aiding the health of the mammalian.3 Although autophagy is viewed as a survival assisting mechanism, just like apoptosis excessive autophagy leads to cell death. It can be induced by both extra cellular and intercellular signals.3 Due to its stress stimuli response, prolonged exposure to the signals will result in the development of diseases. One of the common branches of diseases caused by excessive cell death are the neurodegenerative diseases.
Neurodegenerative diseases
Neuro degeneration is a major mechanism of disease in the nervous system responsible for a range of diseases from small stroke to chronic Parkinson’s and Alzheimer’s.4 Continued research into cell suicide has revealed greatly on the origins of neurodegenerative diseases. Research has suggested that these diseases are caused by too much PCD.1 Mutations in the mechanisms of PCD has resulted in the degeneration of useful cells. Autophagy has been involved in the development of Alzheimer’s. The failure of lysosome function in proteolysis results in accumulation of autolysosomes during autophagy. This has been observed many times and the development of many types of Alzheimer’s has been a consequence of inhibition of lysosome function.6 Autophagy has been excessively induced in experiments to understand where the disease initiating step lies. The observation have implied that the defect lies in the autolysosomal maturation and substrate proteolysis. This defect causes an accumulation of organelles and transport failure. Similar observations have been seen in other neurodegenerative diseases.6
Parkinson’s is a neurodegenerative movement disorder. The neurodegeneration in Parkinson’s has been implicated with the degeneration of irreversibly damaged mitochondria by autophagy. The protective pathway of the mitochondria responsible for defence against mitochondrial damage and dysfunction is disrupted thus resulting in the accumulation of protein complexes which initiate miatophagy.6 There are also implications of oxidative stress and selective dopamine neuron degeneration.6 Excess Dopamine can cause oxidative damage which brings about the mechanism for cell death as mentioned before in the essay. Hyperactivity of cell death mechanisms bring about these degenerative diseases however some diseases are initiated by insufficient cell death.
Insufficient cell death
In some diseases there is insufficient cell death resulting in the formation of a tumor. Cancer is developed as a result of resistance to multiple cell death mechanisms. A mutation in the PCD regulation gene results in uncontrolled cell cycle thus large quantities of useless cells are generated using the nutrients which are available for the growth of healthy cells.
Therapeutic implications
The vital role of cell death in health and disease discussed in the essay and many more have promoted research into curing these diseases by manipulating PCD. Experiments have observed the impact of inhibiting cell death and inducing cell death in different situations. For the neurodegenerative diseases caused by accumulation of proteins and defective function of the lysosome, researchers have observed the impact of drugs which can aid the function of lysosomes by helping the transportation of the damaged organelles and accumulated proteins. On the other hand the therapeutic potential of cell death in cancer has examined inducing cell death in cancer cells through the apoptotic pathways. Targeting mitochondria to induce PCD as well as targeting apoptosis inhibitors involved in the development of cancer have been looked at as important therapeutic strategies.1 All studies and research has concluded the importance of regulated cell death in the body.