Abstract tend to make them quite unstable. These


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

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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

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 (8) 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. whose aggregation is associated
with PD and AD, respectively, this is similar to the proteins that are
consisting of expanded polyglutamine stretches which cause HD and various
ataxias. Remarkably, the size of proteins in amyloid-forming disease is quite
small, contain about 100 amino acids in length, and the disorder occurs in their
?-synuclein and tau (non-aggregated state (2). There is no unique
sequence have been found in these proteins which support the hypothesis that many
proteins have ability to undergo fibrillar ?-sheet aggregation (12–13). The
size of amyloid fibrils is range between 7–13 nm in diameter and several microns
in length. Basically, they form of twist protofilaments around each other or as
flat ribbons. Interestingly, the fibrils like steel in terms of the strength (12),
which is responsible to their extended arrangement of hydrogen-bonded ?-sheets.
In fact, the native form of protein molecule is less stable than the amyloid

The cryo–electron microscopy was behind the
discovery of the interactions occurring in amyloid fibrils, X-ray diffraction
studies of microcrystalline arrays of short peptides and solid-state NMR
analysis. Eisenberg & Saway (3) used highly focused X-ray microbeams at high
resolution to study wide range of amyloid microcrystals, this illustrated n-register
alignment of the ?-strands in the ?-sheet to optimize the tight interdigitation
and the intermolecular interactions of side chains within such pairs. To
overcome the twisting architecture of fibrils a small peptide segment is used
to form amyloid fibrils if not presents to forming crystals. The amyloid
protofilament contains two flat ?-sheets forming a so-called steric zipper and
extending throughout the length of the crystal, some 50,000 layers of short
segments. This primary structure identifies the myloidogenic segments in other
proteins in vitro,

The toxicity of Amyloid aggregation is high to
cells particularly to neurons, this not well understood. The structural
properties of the aggregates have toxic effects. the proteins of disease frequently
aggregate to soluble oligomers which are considered the toxic species (Figure
1). The oligomers expose hydrophobic properties of amino acid residues and
unpaired ?-strands (sticky surfaces(7), these features provide the ability to
disturb phospholipid bilayers (12) and involve in abnormal interactions with many
cellular proteins (10). The normal structure of the fibrils contains these dangerous
surfaces, this explaining why the soluble oligomers are much more interactive
than fibrils.  

However, the fibril contributes to pathology
by both generating oligomers through fragmentation and secondary nucleation and
by stably sequestering key cellular factors (12, 13). The
metastable proteins are often targeted by toxic aggregates; they are present
at the unstructured regions and low amino acid complex, can distinguish many
RNA-binding proteins (9,13). Accordingly,

There is an interferes between protein
aggregation with nucleocytoplasmic RNA transport and RNA homeostasis (6,11).

Many studies have proven that the protein
degradation can inhibited by the aggregates proteasome and autophagy systems (6) and can isolate chaperone components(4,13).

Proteostasis decline and symptom as a result
of interferes between aggregation with protein quality control.

Aggregate is essential to determine cell
viability and the life span of model organisms.

Recent study by Frydman and colleagues (10),
noted that there is difference between protein aggregation in the cell and
aggregation in vitro which mean that cells contain complex mechanisms that
involve particular chaperon proteins, for instance the small heat shock protein
Hsp42 (6), have been developed to minimize the toxic effects exerted by soluble
oligomers (8). Actively sequester surplus and misfolded proteins into transient
or stable deposits when their timely degradation fails. These mechanisms, which
involve specific chaperone proteins like the small heat shock protein Hsp42 (7),
have apparently evolved to reduce the toxic effects exerted by soluble
oligomers (13).

These compartments include the insoluble
protein deposit (IPOD) which discovered in the yeast cells (12). The IPOD terminates
the toxic amyloid and prion proteins in the cell periphery near the vacuole (8)
this equivalent to the mammalian cells aggresome as a site of aggregate
sequestration (11).  

In the transient sequestration the
compartments are called Q-bodies and the juxtanuclear quality control
compartment (JUNQ) (4). The Q-bodies present immediately when protein
misfolding, for instance, under stress they concentrate in the JUNQ in case of degradation,
for instance, under stress they concentrate in the JUNQ in case of degradation
if the ubiquitin proteasome system fails

Other misfolded proteins is cytosolic, potentially
routed to an intranuclear quality control compartment (INQ) (7), which play
pivotal role in degradation of cytosolic proteins and quality control (3, 11).

In conclusion, the massive development that
has been made in last few years in terms of discovering the structure of
pathological protein aggregates and their mechanisms of toxicity. Together with
explaining the relationship between the effective proteostasis network and misfolded
proteins, to find way to prolong the healthy life span.