6-clinical examples on protein abnormalities 14-11-2011

8/3/2019 6-Clinical Examples on Protein Abnormalities 14-11-2011

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Clinical Examples on

Protein Abnormalities


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protein53P(tumour suppressor protein)

= p53 is made up of 393 aa is a transcriptionalfactor

= Not important for cell growth or development

= The main role of p53 in the cell is to regulate thecellular response to internal and external stresssignals through regulation of cell cycle arrest andapoptosis

= stress signals that activate p53 includingDNA damage, hypoxia (oxygen deficiency),growth factors, cell-cell contact, and activatedoncogenes.


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53p

=p53 is the most mutated gene in humancancer

p53 has 75%-80% mutations in colon tumours

50-60% of all human cancers=Mutations in p53 lead to survival of cells with

damaged DNA that may lead totransformation of normal cell to cancer cell.

=p53 plays a crucial role in cellular response tochemotherapy and radiotherapy.


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protein production53Regulation of p

=p53 protein is expressed at very low levels in normal

cells because it is extremely unstable and rapidlydegraded

=Murine Double Minute-2 (Mdm2) protein which is a

product of proto-oncogenes causes thedegradation of p53

=Under stress conditions stabilizations and translationtranslational-postincrease through53of p

.modificationPost-translational modification, like phosphorylation,modifies p53 so that it is no more recognised byMdm2.


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, life or death decision53p

activated p53 accumulates in the nucleus and causescell cycle arrest at G1 or G2 phase to permit DNA repair

p53 controls G1 arrest through the activation of p21gene

p53 controls G2 arrest through the activation of 14-3-3gene.

However, the mechanism by which p53 choosesbetween growth arrest and apoptosis is not known.Extensive research efforts show that several factorsincluding the following may influence the choice:

(1) Cell type

(2) Oncogenic composition of the cell

(3) The intensity of the stress conditions.

(4) The level of p53 expression and its interaction withspecific proteins.


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Cell Cycle


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Alzheimer's disease (AD)

= Named after Dr. Alois Alzheimer, a German doctor

= Alzheimers disease (AD) is an irreversible,progressive brain disease that slowly

skills and, thedestroys memory and thinking

of dailysimplest tasksability to carry out the).dementialiving (

= In most people AD, appear after age 60

=The causes that starts the AD process is notknown, but damages to the brain begin asmany as 10 to 20 years before any obvioussigns of forgetfulness appear.


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Hallmarks of ADThere are three major hallmarks in the brain

that are associated with AD disease :

1- Amyloid plaques

2- Neurofibrillary tangles

3- Loss of connections between cells


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Amyloid PlaquesAmyloid precursor protein (APP), the starting point foramyloid plaques, is one of many proteins associated

with the cell membraneAmyloid plaques are found between brains nervecells.Plaques consist of largely insoluble and hard deposits

. It is not know whether amyloidamyloid-betacalledplaques themselves cause AD or whether they are aby-product of the AD processSpecific enzymes cleave APP into separate fragmentsincluding alpha secretase, beta-secretase, and

gamma-secretase.Depending on which enzyme is involved and thesegment of APP where the cleaving occurs, APP

pathways:one of twoprocessing can follow


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Normal and Alzheimer's neuron


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1- In the unharmful pathway,

alpha-secretase cleaves the APP moleculewithin the portion that has the potential tobecome beta-amyloid. This eliminates theproduction of the beta-amyloid peptide andthe potential for plaque build up. The

cleavage releases from the neuron a fragmentcalled soluble Amyloid Precursor Protein(sAPP), which has beneficial properties,such as promoting neuronal growth and

survival.The remaining attached APP fragment in the

neurons membrane, is then cleaved by

gamma-secretase.


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Amyloid precursor protein (APP)


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The benign pathway


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2- In the harmful pathwaybeta-secretase first cleaves the APP molecule at

one end of the beta-amyloid peptide, releasing

sAPP from the cell.Gamma-secretase then cuts the remaining other

end of the beta-amyloid peptide still attached inthe neurons membrane. This cleavages causes

the release of beta-amyloid into the spaceoutside the neuron. These beta amyloid beginsto stick to each other to form oligomers. It is likelythat some oligomers are cleared from the brain.Those that cannot be cleared clump together

to form fibrils. Other proteins and cellularmaterial are added to fibrils which combine tobecome the well-known plaques that arecharacteristic of AD.


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The harmful pathway


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NEUROFIBRILLARY TANGLES-2twisted protein threadsare abnormal collections ofTangles:

found inside nerve cells.

.tauThe main component of tangles is a protein called

, which help transport nutrients and other cellularMicrotubulescomponents.

phosphate, which usually has a certain number ofTaumolecules attached to it, binds to microtubules andappears to stabilize them.

In AD, an abnormally large number of additional phosphatemolecules attach to tau.

As a result of this hyperphosphorylation, taudisengagesfrom the microtubules and begins to come together withother tau threads.These tau threads form structures called paired helicalfilaments, which can become wrapped up with one another,forming tangles within the cell. The microtubules cancollapse in the process that lead to collapsing the neuronsinternal transport network. This collapse damages the ability

of neurons to communicate with each other.


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Tau


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LOSS OF CONNECTION BETWEEN CELLS-3

The third major feature of AD is the gradual loss ofconnections between neurons. Neurons live to

communicate with each other, and this vital functiontakes place at the synapse.Plaques and tangles has provided important insightsinto their possible damage to synapses and on thedevelopment of AD.

The AD process not only inhibits communicationbetween neurons but can also damage neurons tothe point that they cannot function properly andeventually die.

As neurons die throughout the brain, affected regionsbegin to shrink in a process called brain atrophy. Bythe final stage of AD, damage is widespread, andbrain tissue has shrunk significantly.


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Protein Misfolding in AD

In AD, the misfolded proteins are beta-amyloid and acleaved product of tau.

Misfolded proteins then begin to stick together withother misfolded proteins to form insoluble

aggregates, leading to disruption of cellularcommunication, and metabolism, and even to celldeath.

.AD is an active research area around the world


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Cystic Fibrosis Cystic fibrosis is an inherited disease of the mucus

glands that affects many body systems. signs and symptoms include: progressive damage to the

respiratory system and chronic digestive systemproblems.

Cystic fibrosis used to be considered a fatal disease ofchildhood. With improved treatments and better ways to

manage the disease, many people with cystic fibrosisnow live well into adulthood. Adults with cystic fibrosis experience medical problems

affecting the respiratory, digestive, and reproductivesystems. For example, most men with cystic fibrosis are

unable to father children (infertile) because the tubesthat carry sperm (the vas deferens) are blocked bymucus and do not develop properly. This condition isknown as congenital bilateral absence of the vasdeferens (CBAVD). Infertility is also possible, though

less common, in women with cystic fibrosis.

Wh t l t d t ti fib i ?


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What genes are related to cystic fibrosis? Mutations in the CFTR gene (cystic fibrosis transmembrane

conductance regulator) cause cystic fibrosis. The CFTR geneprovides instructions for making a channel that transports negativelycharged particles called chloride ions into and out of cells. The flow

of chloride ions helps control the movement of water in tissues,which is necessary for the production of thin, freely flowing mucus.

Mutation in the CFTR leads to the deletion of a crucial amino acidfrom the protein involved in the disease and when the protein lacks

this amino acid, it doesn't fold into its correct shape and loses itsfunction. This altered shape prevents the mutant proteins frombinding to ATP.

How do people inherit cystic fibrosis? This condition is inherited in an autosomal recessive pattern, which

means both copies of the gene in each cell have mutations. Theparents of an individual with an autosomal recessive condition eachcarry one copy of the mutated gene, but they typically do not showsigns and symptoms of the condition.

6-clinical examples on protein abnormalities 14-11-2011

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