Download pdf - Protein misfolding and related disease

7/28/2019 Protein misfolding and related disease.

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A Protein is a polymer of amino acids which contains a constant

backbone of repeating units with a variable side chain attached toeach unit of backbone. Proteins all have the same backbone, theside chains are what distinguish proteins and give their individual

characteristics.Proteins under ideal conditions such as suitable solvent andtemperature will adopt a stable structure called the native state.Proteins exist in a primary, secondary, tertiary and quaternarystructure.


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ALPHA HELIX

BETA SHEETS

TERTIARY STRUCTURE

QUATERNARY STRUCTURE


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How and whether a protein folds in vivo areinfluenced primarily by its amino acid sequenceand the cellular environment surrounding thepolypeptide chain1. Protein folding in the cell

occurs either in the cytoplasm or within thesecretory ATP-dependent chaperones in thecytoplasm and the lumen of the endoplasmicreticulum (ER) collaborate to give a polypeptidechain several opportunities to fold. If folding isunsuccessful, the polypeptide is directed to theproteasomea large multisubunit proteasefordegradation. Ensuring accuracy in protein foldingis crucial for maintaining proper cellular function.


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Proteolytic cleavage breaks down proteins

Extracellularly

Intracellularly

Degradation of protein serves a number of functions

IMPROPER FOLDED PROTEINS ARE MAJORLYDEGRADED BY UBIQUINTINPROTEOSOMEPATHWAY


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conjugation of multiple ubiquitin moieties to thesubstrate and degradation of the tagged protein by the

downstream 26S proteasome complex


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The ubiquitin proteolytic pathway. 1: Activation of ubiquitin bythe ubiquitin-activating enzyme E1, a ubiquitin-carrier protein, E2(ubiquitin-conjugating enzyme, UBC), and ATP. The product ofthis reaction is a high-energy E2ubiquitin thiol esterintermediate.

2: Binding of the protein substrate, via a defined recognitionmotif, to a specific ubiquitin-protein ligase, E3.

3: Multiple (n) cycles of conjugation of ubiquitin to the targetsubstrate and synthesis of a polyubiquitin chain. E2 transfers thefirst activated ubiquitin moiety directly to the E3-bound substrate,and in following cycles, to previously conjugated ubiquitin

moiety. Direct transfer of activated ubiquitin from E2 to the E3-bound substrate occurs in substrates targeted by RING finger E3s.

3: As in3, but the activated ubiquitin moiety is transferred fromE2 to a high-energy thiol intermediate on E3, before itsconjugation to the E3-bound substrate or to the previouslyconjugated ubiquitin moiety. This reaction is catalyzed by HECTdomain E3s.

4: Degradation of the ubiquitin-tagged substrate by the 26Sproteasome complex with release of short peptides.

5: Ubiquitin is recycled via the activity of deubiquitinatingenzymes (DUBs).


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Complete, rapid, and sustained termination of

the process

Ubiquitination and proteolysis of activators evenmay stimulate transcriptional activity

UPP selectively eliminates abnormally folded or

damaged proteins

APOPTOSIS


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The conversion of a protein into astructure that differs from its native state.

The improper foldings are generallyeliminated or degraded by ubiquintin-proteasome pathway to ensure high fidelityof protein expression but sometimesproteins escape this process leading toprotein aggregation like

Loop sheet polymer

Amyloid fibrils


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Graph representing folding and misfolding states.


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Protein aggregates having a cross- structure andother characteristics, e.g., specific dye-binding.

These misfolded structures alter their properconfiguration such that they erroneously interactwith one another or other cell components forminginsoluble fibrils. They have been associated with thepathology of more than 20 serious human diseases

in that, abnormal accumulation of amyloid fibrils inorgans may lead to amyloidosis, and may play arole in various neurodegenerative disorders.
http://en.wikipedia.org/wiki/Fibrilhttp://en.wikipedia.org/wiki/Amyloidosishttp://en.wikipedia.org/wiki/Neurodegenerativehttp://en.wikipedia.org/wiki/Neurodegenerativehttp://en.wikipedia.org/wiki/Amyloidosishttp://en.wikipedia.org/wiki/Fibril


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A


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The fibrils can be imaged in vitro using transmission electronmicroscopy (TEM) or atomic force microscopy (AFM). Theseexperiments reveal that the fibrils usually consist of a number(typically 26) of protofilaments, each about 25 nm in diameter.These protofilaments twist together to form ropelike fibrils that aretypically 713 nm wide or associate laterally to form long ribbonsthat are 25 nm thick and up to 30 nm wide. X-ray fiber diffraction

data have shown that in each individual protofilament theprotein or peptide molecules are arranged so that thepolypeptide chain forms -strands that run perpendicular to thelong axis of the fibril.


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The largest group of misfolding diseases, however, is

associated with the conversion of specific peptides

or proteins from their soluble functional states

ultimately into highly organized fibrillar aggregates.These structures are generally described as

amyloid fibrils or plaques when they accumulate

extracellularly, whereas the term intracellular

inclusions has been suggested as moreappropriate when fibrils morphologically and

structurally related to extracellular amyloid form

inside the cell.


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Neurodegenerative disordermost common cause of dementia in elderly

Clinically, apparent as insidious

impairment of higher intellectual function,

with alteration in mood and behavior.

Later, progressive disorientation, memory loss

and aphasia, indicate severe cortical

dysfunction

Later, patient becomes disabled, mute and

immobile


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--Initial

Forgetfulness; other memory disturbances

Language deficits Loss of learned motor skills

Loss of mathematical skills

--Finally

Patient become mute; unable to walk


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Individuals with Downs syndrome contain an extra copy ofchromosome 21, (3 in total), and if they survive until middle age, there isalmost a definite probability they will develop AD . This chromosomecontain a gene linked to early-onset AD.

Chromosome 14 was also found to have a gene (S182) responsible forearly-onset AD, as well as chromosome 1, which contains a gene (STM2)

responsible for early-onset AD. Other chromosomes are being studied foridentification of AD causing genes.

Amyloid deposits, (A), in the brain of an individual with AD havepeptide deposits of approximately 40-residues long. Amyloid depositsare the product of their precursor, Amyloid precursor protein (APP),resulting from the action of proteases - and -secretase.

Aare produced with variable lengths of 40 and 42 residues long, A40

and A42. The predominant Aproduced in a normal individual is A40.Mutations in the APP gene on chromosome 21 either increases theamyloid levels or just A42 alone.

The initial deposits of A42 are able to promote the further deposition ofboth A42 and A40, all these amyloid deposits cause the widespreadatrophy.


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AD, the most prevalent dementia affecting almost 2% of thepopulation in the western world, The risk of developing ADdramatically increases in people over 70 years.

The most reliable diagnosis of AD is possible, unfortunately, whenthe individual has deceased, by conducting a post-mortem to

identify amyloid deposits and neurofibrillary tangles and plaquesin the brain .

From post-mortem examinations of brains from AD patients,abnormalities can be seen such as wasting away of primarilyfrontal and temporal gyri (up to 20%) and ventricleenlargements. Although, this may be due to ageing.

The amyloid deposits cause the widespread atrophy (wastingaway) of the cerebral cortex, and also other areas, such as thehippocampus. Tangles and plaques are formed from discardedparts of neurons that have died or shrunk. Tangles are structuresformed from degenerating neuronal cell bodies and plaquesare structures formed from degenerating axons and dendrites


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Parkinson disease is a braindisorder. It occurs when certainnerve cells (neurons) in a part ofthe brain called the substantianigra die or become impaired.Normally, these cells produce a

vital chemical known asdopamine. Dopamine allowssmooth, coordinated function ofthe body's muscles andmovement. Whenapproximately 80% of the

dopamine-producing cells aredamaged, the symptoms ofParkinson disease appear.


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The key signs of Parkinson disease are: Tremor (shaking) Slowness of movement

Rigidity (stiffness) Difficulty with balanceOther signs of Parkinson diseasemay include: Small, cramped handwriting

Stiff facial expression Shuffling walk Muffled speech Depression


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Aggregating protein is alpha-synuclein.

Protein is natively unfolded and it has 140

residues. partial neutralization of the negative

charge of -synuclein will stimulate

aggregation on a purely electrostatic

argument, pairs of variants with a similar netcharge but opposite signs (for example+3

and 3) aggregate more rapidly when the

NAC region is unprotected .


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Aggregation propensity profile (red line) for -synuclein. The largeregion of the protein thought to be structured in the fibrils (pale gray) isshown and includes all the peaks in the profile. The highly

amyloidogenic NAC region (light blue) and the 6979 region(darkblue), found to be a particularly amyloidogenic segment withinthe NAC region and containing the most prominent peak in the profile


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The word prion is derived from the word infection and protein .

Prion diseases ortransmissible spongiform encephalopathies (TSEs)

are a family of rare progressive neurodegenerative disorders ( loss of

structureorfunction of neurons, including death of neurons. ) that affect

both humans and animals.

it is known as "mad cow disease" in cattle and Creutzfeldt -Jakob

disease (CJD) in humans.


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Prions propagate by transmitting a misfolded protein state. When a prion enters a healthy organism, it induces existing,

properly folded proteins -which is found most abundantly inthe brain- to convert into the disease-associated, prion form.

Alteration in the conformation of the protein where normal -helix structure is converted to -sheet structure. the prion acts as a template to guide the misfolding of more

protein into prion form. These newly formed prions can then go on to convert more

proteins themselves; this triggers a chain reaction thatproduces large amounts of the prion form.

Aggregations of these abnormal isoforms form highlystructured amyloid fibers, which accumulate to form plaques.
http://en.wikipedia.org/wiki/Alpha_helixhttp://en.wikipedia.org/wiki/Beta_sheethttp://en.wikipedia.org/wiki/Alpha_helixhttp://en.wikipedia.org/wiki/Alpha_helixhttp://en.wikipedia.org/wiki/Alpha_helixhttp://en.wikipedia.org/wiki/Beta_sheethttp://en.wikipedia.org/wiki/Beta_sheethttp://en.wikipedia.org/wiki/Beta_sheethttp://en.wikipedia.org/wiki/Beta_sheethttp://en.wikipedia.org/wiki/Beta_sheethttp://en.wikipedia.org/wiki/Alpha_helixhttp://en.wikipedia.org/wiki/Alpha_helixhttp://en.wikipedia.org/wiki/Alpha_helix


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All known mammalian prion diseases arecaused by the so-called prion protein, PrP.

The endogenous, properly folded, form is

denoted PrPC (for Common or Cellular) whilethe disease-linked, misfolded form is denotedPrPSc (for Scrapie )


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Three-dimensional structure of PrP C (left) andproposed 3D structure of PrP Sc (right). Alphahelices are indicated in green while beta sheetsare indicated in blue. PrP C is composedprimarily of alpha helices while PrP Sc iscomposed primarily of Beta pleated sheets.


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Left: normal prion protein (coloured green) in non-infected mouse cell cultures. Right: misfolded prion form (coloured green) in

infected cell which accumulate primarily in vesicleswithin the cell. Cell nuclei are edepicted in blue.


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POSTMORTEMBRIAN TISSUE


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Personality changes Psychiatric problems Depression Lack of coordination

Unsteady gait

Myoclonus Unusual sensations

Insomnia Confusion Memory problems Severe mental impairment Inability to move Inability to speak

Symptoms in humans
http://www.rightdiagnosis.com/sym/personality_change.htmhttp://www.rightdiagnosis.com/sym/psychological_problems.htmhttp://www.rightdiagnosis.com/sym/depressive_symptoms.htmhttp://www.rightdiagnosis.com/sym/coordination_problems.htmhttp://www.rightdiagnosis.com/sym/unsteady_gait.htmhttp://www.rightdiagnosis.com/sym/myoclonus.htmhttp://www.rightdiagnosis.com/sym/sensations.htmhttp://www.rightdiagnosis.com/sym/insomnia.htmhttp://www.rightdiagnosis.com/sym/confusion.htmhttp://www.rightdiagnosis.com/sym/memory_problems.htmhttp://www.rightdiagnosis.com/sym/cognitive_impairment.htmhttp://www.rightdiagnosis.com/sym/inability_to_move.htmhttp://www.rightdiagnosis.com/sym/inability_to_speak.htmhttp://www.rightdiagnosis.com/sym/inability_to_speak.htmhttp://www.rightdiagnosis.com/sym/inability_to_move.htmhttp://www.rightdiagnosis.com/sym/cognitive_impairment.htmhttp://www.rightdiagnosis.com/sym/memory_problems.htmhttp://www.rightdiagnosis.com/sym/confusion.htmhttp://www.rightdiagnosis.com/sym/insomnia.htmhttp://www.rightdiagnosis.com/sym/sensations.htmhttp://www.rightdiagnosis.com/sym/myoclonus.htmhttp://www.rightdiagnosis.com/sym/unsteady_gait.htmhttp://www.rightdiagnosis.com/sym/coordination_problems.htmhttp://www.rightdiagnosis.com/sym/depressive_symptoms.htmhttp://www.rightdiagnosis.com/sym/psychological_problems.htmhttp://www.rightdiagnosis.com/sym/personality_change.htm


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Huntingtons Disease is a genetic diseasewhere nerve cells deteriorate in the brain.People diagnosed with this disease typically

die 10 to 30 years after showing symptoms;however, most people are not aware ofhaving the disease.

Huntingtons Disease is a genetic disease, so it is

given from the parent to the child. This is referredto as autosomal dominant because only oneparent needs to gene that codes for the disease topass it on to their child.


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Huntingtons Disease occurs because of a genetic defecton chromosome . This defect makes a CAG repeat occurmore rapidly than it typically should. Normally the CAG

repeat occurs 10 to 35 times, yet the defect causes it torepeat 36 to 120 times, which is abnormal. The greaterthe number of CAG repeats, the higher the chance ofreceiving the disease.


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In Vitro Fertilization with Pre- Implantation

Screening is a process in which embryos are

screened for Huntingtons Disease, and thosethat do not have the CAG mutation will be

implanted into the woman for fertilization.

This minimizes the chance of passing on the

disease to the children.


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