A Protein is a polymer of amino acids which contains a constant backbone of repeating units with a variable side chain attached

to each unit of backbone. Proteins all have the same backbone, the side chains are what distinguish proteins and give their individual characteristics. Proteins under ideal conditions such as suitable solvent and temperature will adopt a stable structure called the native state. Proteins exist in a primary, secondary, tertiary and quaternary structure.

ALPHA HELIX BETA SHEETS TERTIARY STRUCTURE QUATERNARY STRUCTURE

How and whether a protein folds in vivo are influenced primarily by its amino acid sequence and the cellular environment surrounding the polypeptide chain1. Protein folding in the cell occurs either in the cytoplasm or within the secretory ATP-dependent chaperones in the cytoplasm and the lumen of the endoplasmic reticulum (ER) collaborate to give a polypeptide chain several opportunities to fold. If folding is unsuccessful, the polypeptide is directed to the proteasome a large multisubunit protease for degradation. Ensuring accuracy in protein folding is crucial for maintaining proper cellular function.

Proteolytic cleavage breaks down proteins Extracellularly Intracellularly Degradation of protein serves a number of functions

IMPROPER FOLDED PROTEINS ARE MAJORLY DEGRADED BY UBIQUINTIN PROTEOSOME PATHWAY

 conjugation of multiple ubiquitin moieties to the substrate and degradation of the tagged protein by the downstream 26S proteasome complex

The ubiquitin proteolytic pathway. 1: Activation of ubiquitin by the ubiquitin-activating enzyme E1, a ubiquitin-carrier protein, E2 (ubiquitin-conjugating enzyme, UBC), and ATP. The product of this reaction is a high-energy E2ubiquitin thiol ester intermediate. 2: Binding of the protein substrate, via a defined recognition motif, to a specific ubiquitin-protein ligase, E3. 3: Multiple (n) cycles of conjugation of ubiquitin to the target substrate and synthesis of a polyubiquitin chain. E2 transfers the first 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 E3bound substrate occurs in substrates targeted by RING finger E3s. 3: As in3, but the activated ubiquitin moiety is transferred from E2 to a high-energy thiol intermediate on E3, before its conjugation to the E3-bound substrate or to the previously conjugated ubiquitin moiety. This reaction is catalyzed by HECT domain E3s. 4: Degradation of the ubiquitin-tagged substrate by the 26S proteasome complex with release of short peptides. 5: Ubiquitin is recycled via the activity of deubiquitinating enzymes (DUBs).

Complete, rapid, and sustained termination of the process Ubiquitination and proteolysis of activators even may stimulate transcriptional activity UPP selectively eliminates abnormally folded or damaged proteins APOPTOSIS

The conversion of a protein into a structure that differs from its native state.
The improper foldings are eliminated or degraded by proteasome pathway to ensure of protein expression but proteins escape this process protein aggregation like Loop sheet polymer Amyloid fibrils generally ubiquintinhigh fidelity sometimes leading to

Graph representing folding and misfolding states.

Protein aggregates having a cross- structure and other characteristics, e.g., specific dye-binding. These misfolded structures alter their proper configuration such that they erroneously interact with one another or other cell components forming insoluble fibrils. They have been associated with the pathology of more than 20 serious human diseases in that, abnormal accumulation of amyloid fibrils in organs may lead to amyloidosis, and may play a role in various neurodegenerative disorders.

The fibrils can be imaged in vitro using transmission electron microscopy (TEM) or atomic force microscopy (AFM). These experiments 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 are typically 713 nm wide or associate laterally to form long ribbons that are 25 nm thick and up to 30 nm wide. X-ray fiber diffraction data have shown that in each individual protofilament the protein or peptide molecules are arranged so that the polypeptide chain forms -strands that run perpendicular to the long axis of the fibril.

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 more appropriate when fibrils morphologically and structurally related to extracellular amyloid form inside the cell.

 Neurodegenerative disorder most 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

-- Initial Forgetfulness; other memory disturbances Language deficits Loss of learned motor skills Loss of mathematical skills -- Finally Patient become mute; unable to walk

Individuals with Downs syndrome contain an extra copy of chromosome 21, (3 in total), and if they survive until middle age, there is almost a definite probability they will develop AD . This chromosome contain a gene linked to early-onset AD. Chromosome 14 was also found to have a gene (S182) responsible for early-onset AD, as well as chromosome 1, which contains a gene (STM2) responsible for early-onset AD. Other chromosomes are being studied for identification of AD causing genes. Amyloid deposits, (A), in the brain of an individual with AD have peptide deposits of approximately 40-residues long. Amyloid deposits are the product of their precursor, Amyloid precursor protein (APP), resulting from the action of proteases - and -secretase. A are produced with variable lengths of 40 and 42 residues long, A40 and A42. The predominant A produced in a normal individual is A40. Mutations in the APP gene on chromosome 21 either increases the amyloid levels or just A42 alone. The initial deposits of A42 are able to promote the further deposition of both A42 and A40, all these amyloid deposits cause the widespread atrophy.

AD, the most prevalent dementia affecting almost 2% of the population in the western world, The risk of developing AD dramatically increases in people over 70 years. The most reliable diagnosis of AD is possible, unfortunately, when the individual has deceased, by conducting a post-mortem to identify amyloid deposits and neurofibrillary tangles and plaques in the brain . From post-mortem examinations of brains from AD patients, abnormalities can be seen such as wasting away of primarily frontal and temporal gyri (up to 20%) and ventricle enlargements. Although, this may be due to ageing. The amyloid deposits cause the widespread atrophy (wasting away) of the cerebral cortex, and also other areas, such as the hippocampus. Tangles and plaques are formed from discarded parts of neurons that have died or shrunk. Tangles are structures formed from degenerating neuronal cell bodies and plaques are structures formed from degenerating axons and dendrites

Parkinson disease is a brain disorder. It occurs when certain nerve cells (neurons) in a part of the brain called the substantia nigra die or become impaired. Normally, these cells produce a vital chemical known as dopamine. Dopamine allows smooth, coordinated function of the body's muscles and movement. When approximately 80% of the dopamine-producing cells are damaged, the symptoms of Parkinson disease appear.

The key signs of Parkinson disease are: Tremor (shaking) Slowness of movement Rigidity (stiffness) Difficulty with balance Other signs of Parkinson disease may include: Small, cramped handwriting Stiff facial expression Shuffling walk Muffled speech Depression

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 net charge but opposite signs (for example+3 and 3) aggregate more rapidly when the NAC region is unprotected .

Aggregation propensity profile (red line) for -synuclein. The large region of the protein thought to be structured in the fibrils (pale gray) is shown 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 within the NAC region and containing the most prominent peak in the profile

The word prion is derived from the word infection and protein . Prion diseases or transmissible spongiform encephalopathies (TSEs) are a family of rare progressive neurodegenerative disorders ( loss of structure or function 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.

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 in the 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 that produces large amounts of the prion form. Aggregations of these abnormal isoforms form highly structured amyloid fibers, which accumulate to form plaques.

All known mammalian prion diseases are caused by the so-called prion protein, PrP. The endogenous, properly folded, form is denoted PrPC (for Common or Cellular) while the disease-linked, misfolded form is denoted PrPSc (for Scrapie )

Three-dimensional structure of PrP C (left) and proposed 3D structure of PrP Sc (right). Alpha helices are indicated in green while beta sheets are indicated in blue. PrP C is composed primarily of alpha helices while PrP Sc is composed primarily of Beta pleated sheets.

Left: normal prion protein (coloured green) in noninfected mouse cell cultures. Right: misfolded prion form (coloured green) in infected cell which accumulate primarily in vesicles within the cell. Cell nuclei are edepicted in blue.

POSTMORTEM BRIAN TISSUE

Symptoms in humans

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

Huntingtons Disease is a genetic disease where 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 of having the disease. Huntingtons Disease is a genetic disease, so it is given from the parent to the child. This is referred to as autosomal dominant because only one parent needs to gene that codes for the disease to pass it on to their child.

Huntingtons Disease occurs because of a genetic defect on chromosome . This defect makes a CAG repeat occur more rapidly than it typically should. Normally the CAG repeat occurs 10 to 35 times, yet the defect causes it to repeat 36 to 120 times, which is abnormal. The greater the number of CAG repeats, the higher the chance of receiving the disease.

In Vitro Fertilization with Pre- Implantation Screening is a process in which embryos are screened for Huntingtons Disease, and those that 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.