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Abstract biological activities of proteins tend to make them

Abstract

Commonly protein molecules folds into 3-dimensional form in order to be
perform its function. However, the biological activities of proteins tend to
make them quite unstable. These unstable proteins populate misfolded chains to
form toxic aggregates, consisting of fibrillar amyloid deposits and soluble
oligomers, which are causing many pathologies such as Alzheimer and Parkinson
disease. All cells have an extensive protein homeostasis to prevent and
regulate protein aggregation by comprising molecular chaperones and other
factors.

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During aging these defense systems are weakening easing the
manifestation of aggregate deposition diseases. This paper is addressing the
structure of misfolded protein aggregation and the mechanism of its disease,
moreover discuss the recent strategies on how cells neutralize toxic aggregates
by sequestering them in specific cellular locations.

 

 

 

 

 

 

 

 

 

 

 

 

The nature of Proteins molecules are the most versatile among other
macromolecules. The mammalian cells contain between 10,000 and 20,000 diverse
proteins. The balance between protein synthesis, degradation and folding must
be controlled properly to maintain proteome integrity and cellular health.

The information that specifies the compactly folded structure of a
protein, required for its biological activity, is encoded in the linear amino
acid sequence of the newly synthesized polypeptide chain (1), which may be up to several thousand amino acids
in length. However, the number of conformations even a small polypeptide of ?100 amino acids can adopt is astronomically large (?1030) (2). Moreover, the biologically
active conformation (the native state), though thermodynamically favorable, is
often only marginally stable under physiological conditions. It is not
surprising, therefore, that the folding process is error prone, giving rise to
misfolded states and off-pathway aggregates (Figure 1). Scholars prove that
most of proteins require assistance from chaperones to fold effectively at a
biological rate (3). To prevent misfolding and
aggregation the chaperones on the ribosome gather with the nascent polypeptide
chain during translation. These chaperones typically act by transiently
shielding the hydrophobic amino acid residues that are exposed by proteins in
their non-native conformations but are buried in the native state. They cooperate
with machineries of protein degradation in a large protein homeostasis or
proteostasis network (4–6).

 

An expanding list of pathologies has been
linked the Irregular folding. There are two groups of diseases loss-of-function
and toxic gain-of-function diseases. The loss-of-function group distinct by protein
dysfunction resulting from mutations (single nucleotide polymorphisms) that may
render proteins metastable and prone to degradation, such as the case of a wide
range of metabolic defects and cystic fibrosis (7). In the toxic
gain-of-function diseases of the second group, cellular toxicity associated
with the metastable proteins undergo aggregation in a process associated. These
pathologies include a list of diseases such as Alzheimer disease (AD) and
Parkinson disease (PD), the neurodegenerative diseases that cripple our aging
societies, as well as certain forms of heart disease and cancer and type II
diabetes. Heritable mutations may be causes aggregation in proteins disease, for
instance the case of early onset AD and D and huntington disease (HD). However,
most of cases are manifest and stochastic in an

age-dependent manner, apparently facilitated through
a decline in the capacity of the proteostasis network that occurs during aging
(6, 8, 9).

Aggregates formation and their structural
properties:

Exposing the hydrophobic amino acid residues
and regions of unstructured polypeptide backbone to the solvent lead to partially
folded or misfolded proteins, which aggregates rich in ?-sheet structure
(Figure 1). While during the correct folding hydrophobic region to stabilize
its compact structure, even though most of the aggregates are amorphous there
is a mall set of non-natives known as amyloid fibrils, this subset forms of ?-strands
running perpendicular to the long fibril axis (cross-? structure) (10). In 1935
William Astbury discovered this unique structure in poached egg white. The age-dependent
neurodegenerative diseases distinguish by the formation of fibrillar aggregates
and their deposition within and around cells.

Chiti &Dobson (12) have noted that the
extracellular space of the nervous system and various organs secret and deposits
several amyloid-forming proteins. Fairly few amyloidogenic polypeptides like ?-synuclein
and tau are cytosolic and form intracellular inclusions. 

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