Cell death and diseases

A)  Neurodegenrative diseases related to cell death,

they are the most common form of diseases caused by an increase in cell death, examples are:

1) Parkinson's Disease (PD):

A neurodegenerative disorder of the central nervous sysytem. It occurs as a result of greatly reduced activity of dopamine-secreting cells due to cell death in the pars compacta region of the substantia nigra, A combination of the reduction of cells and a low level of dopamine in the cells in this part of the brain causes nerve messages to the muscles to become slowed and abnormal, making the victim unable to perform smooth coordinated movements.

This is due to defects in several cellular systems which act as early triggers that start cells down the road towards neuronal death. These include abnormal protein accumulation particularly of alpha-synuclein, altered protein degradation via multiple pathways, mitochondria dysfunction, oxidative stress, neuroinflammation, and dysregulated kinase signalling. As dysfunction in these systems mounts, pathways that are more explicitly involved in cell death become recruited. These include JNK signalling, P53 activation, cell cycle reactivation and signalling through bcl-2 proteins . Eventually neurons become overwhelmed and degenerate, read article here.

                                   

This histological image is showing a positive immunohistochemistry staining for alpha synuclein in a brain cell of the substantia nigra in parkinson's disease. Image in courtesy of http://commons.wikimedia.org/wiki/File:A_synuclein_cortex_DLB.jpg

2) Huntington's Disease (HD):

HD is an inherited neurodegenerative disorder characterized by progressive cell death that predominantly affects basal-ganglia structures, most notably the caudate and putamen. In these regions, gross atrophy, selective loss of medium-sized projection neurons and associated astrocytosis are observed.

The genetic mutation responsible for HD produces an unstable expansion of CAG nucleotide repeats in the gene encoding the cytoplasmic protein huntingtin. This mutation leads to the production of a protein which has different characteristics. this altered form called mHtt ( mutant huntingtin) increases the rate of cell death of certain types of neurons. Regions of the brain have different amounts and reliance on these types of neurons and are affected accordinly.It is believed that increased cell death in the affected areas is due to oxidative stres and neurotoxicity of the mHtt.

 

3) Alzheimer's Disease (AD):

It is a progressive neurodegenerative disorder, which is characterised clinically by dementia and progressive memory loss, pathologically by neuronal degeneration, plaques (insoluble beta-amyloid(A-beta) proteins) and neurofibrillary lesions (abnormally phosphorylated tau proteins). Due to the excess amount of A-beta proteins, multiple cytotic mechanisms which involve increase of intracellular Ca2+ levels, oxidative stress and receptor-mediated activation of cell death cascades is evoked.

The hippocampus is one of the first regions of the brain to be affected in Alzheimer's disease, showing cell loss mainly in the CA1-2 pyramidal cell layers. to learn more about Alzheimer's disease

 Other diseases related to cell death in the brain are:

4) Motor neuron disease:

Which is the death of motor neurons that control essential voluntary muscles activity such as speacking, walking, swallowing etc. when these neurons die the individual becomes unable to perform such actions.

5) Dentatorubral - Pallidoluysian Atrophy (DRPLA):

An autosomal dominant spinocerebrallar degeneration caused by an expression of a CAG nucleotide repeat encoding a polyglutamine tract in the atrophin-1 protein.

 

B) Non Neurodegenerative diseases related to cell death

They are related to a massive decrease in cell death, or nonoccurence of cell death as a whole, examples are:

1) Polydactyly:

Also known as hyperdactyly is a congenital physical anomaly in humans, dogs and cats having supernumerary fingers and toes. in addition to mesodermal cell death, apoptosis is also an important feature of the ectoderm in the Apical Ectodermal Ridge (AER). In mammals apoptosis in the AER is more prominent than in birds and forms well defined foci of cell death. The inhibition or delay of this ectodermal cell death causes an enlargment of the AER followed by an increase in the amount of subridge mesenchyme which results in the induction of polydactyly.

              

This is a picture of a baby's hands showing the occurance of extra digits due to polydactyly. Image in courtesy of http://commons.wikimedia.org//wiki/File:Polydactyly_ECS.jpg?uselang=en-gb

 

2) Cancers:

Cancers are a class of diseases in which a group of cells show uncontrolled growth and decreased rate of cell death. These cells tend to invade and destroy adjacent tissues and sometimes they metastasis to other locations in the body via lymph or blood. One of the fundamental hallmarks of cancers is to avoid apoptosis and continue to proliferate. They do this by acquiring survival strategies to suppress cell death or apoptotic mechanisms.

For example, some B-cell leukemias and lymphomas express high levels of Bcl-2 proteins thus they block apoptotic signals by translocating Bcl-2 gene into an enhancer region for antibody production. Also melanoma which is regarded as one of the most dangerous type of skin cancer acts through inhibiting the expression of Apaf-1 gene and thus avoiding apoptosis. Some cancers cells like lung and colon cancer cells, secrete elevated levels of a soluble "decoy" molecule that binds to Fasl, blocking it from interacting with it's receptor Fas. Other cancer cells express high levels of FasL and can kill any cytotoxic T cells (CTL) that try to kill them because CTL also express Fas.

Also cancers associated with viruses use these viruses as a means to prevent apoptosis fro example: the Human Papilloma Viruses (HPV) that cause cervical cancer, has the ability to produce proteins called E6 and E7 that bind and inactivate the apoptosis promoter p53. Also Epstein-Barr Virus (EBV), that cause mononucleosis and is also associated with some lymphomas, produce a protein similar to Bcl-2 protein. It also produces another protein that causes the cell to increase its own production of Bcl-2 protein. Both actions make the cell more resistant to apoptosis.