Protein Folding, Misfolding,
Aggregation And Amyloid Formation: Mechanisms of A Oligomer Mediated Toxicities
Parveen Salahuddin
Parveen Salahuddin, Distributed
Information Sub-Centre (DISC), Interdisciplinary Biotechnology Unit, Aligarh
Muslim University (A.M.U.), Aligarh, 202002, India
Correspondence to: Parveen Salahuddin, Distributed
Information Sub-Centre (DISC), Interdisciplinary Biotechnology Unit, Aligarh
Muslim University (A.M.U.), Aligarh, 202002, India
Email:
parveensalahuddin@gmail.com
Telephone: +91-571-2721776
Received: January 24, 2015
Revised: April 1, 2015
Accepted: April
6, 2015
Published online:
June 6, 2015
ABSTRACT
Protein folding is
one of the most perplexing problems in molecular biology. Protein folding is a
complex process through which protein molecule acquires unique native structure
which carry out specific biological
function. However, recently it has been recognized that some proteins have no
single well-defined tertiary structure.These proteins are termed intrinsically
disordered protein (IDP) which are involved in regulation and signaling. In
1969, Cyrus Levinthal noted that, because of the very large number of degrees
of freedom in an unfolded polypeptide chain, the protein molecule has an
astronomical number of possible conformations. Hence, from one calculation, for
100 amino acids polypeptide chain, 1011 years will be required for
protein to fold, which is an unrealistic time because in vivo protein folding
occurs in seconds or minutes. This is known as Levinthal paradox. To overcome
Levinthal paradox, several folding models have been proposed. This includes
from classical nucleation-propagation model to folding funnel model. The in
vitro and in vivo conditions of protein folding are not the same.This was
particularly challenged by the discovery of molecular chaperones that assist
in correct folding of protein and
if protein still misfolds it is subjected to proteasomal degradation for the
maintenance of cell homeostasis. Despite of cellular protein quality control
proteins often misfold. This happens due to mutations, changes in environmental
conditions and includes many more factors. These misfolded proteins give rise
to increase population of partially misfolded intermediates which have exposed
hydrophobic residues that interact with complementary intermediates and
consequently results in the formation of oligomers thereby proto-fibrils and
fibrils. These fibrils are deposited in the brain and CNS leading to the
manifestation of neurodegenerative diseases. Keeping above views in mind, in
this review I have focused on, various folding models, folding in the cell,
misfolding, aggregation and mechanism of A fibril formation. Since A oligomers are now
considered as more toxic entities than fibrils. Hence, their mechanisms of
toxicities also form the theme of the review.
© 2015 ACT. All
rights reserved.
Key words: Protein folding; Protein misfolding; Protein
aggregation; A
oligomers; Protein folding models
Salahuddin P. Protein
Folding, Misfolding, Aggregation And Amyloid Formation: Mechanisms of A¦Â Oligomer
Mediated Toxicities. Journal of Biochemistry and Molecular Biology Research 2015; 1(2): 36-45
Available from: URL: http://www.ghrnet.org/index.php/jbmbr/article/view/1027
Abbreviations
A: Amyloid beta;
ATP: Adenosine Tri
Phosphate;
CNS: Central
Nervous System;
IDP: Intrinsically
Disordered Protein;
NMR: Nuclear
Magnetic Resonance;
UV-CD:
Ultraviolt-Circular Dichroism.
INTRODUCTION
Protein folding is a complex process through which protein molecule
acquires unique three-dimensional conformation that carry out specific
biological function. However, recently it has been found that some proteins
have no single unique tertiary structure.These proteins are termed
intrinsically disordered protein (IDP)[1] which are involved in
regulation and signaling. The type of native structure which a protein molecule
adopts is specified in its amino acid sequence[2]. There are several
questions that are related to protein folding. For instance, why should
polypeptide chain fold? The answer is eukaryotic cell cannot accommodate 3-4
million different polypeptides if all of them occur in an unfolded state.
Besides, unfolded proteins will be subjected to enormous proteolytic
degradation hazard. Formation of a crevice or active site in a protein molecule
is inconceivable without protein folding. Protein folding may serve as a model
for delineating molecular basis of protein-mediated morphogenesis of viruses,
subcellular organelles and tissues, because the kind of forces that are
believed to be involved in the self-assembly processes are the same as those
that hold different segments of the polypeptide chain together in the native
state[3]. Protein folding has also applications in genome research,
in the understanding of different pathologies and in the design of novel
proteins with special function.
In 1969, Cyrus
Levinthal noted that, because of the very large number of degrees of freedom in
an unfolded polypeptide chain, the protein molecule has an astronomical number
of possible conformations. Hence, for 100 amino acids polypeptide chain if we
assume only two possible conformations for each residue, then there are 1030
possible conformations for the polypeptide chain.If only 10-11 second is
required to convert one conformation into another, a random search of all
conformations would require 1011 years,which is an unrealistic time
because in vivo protein folding occurs in seconds or minutes. This is known as
Levinthal paradox. To overcome Levinthal paradox, several folding models have
been proposed. This includes from classical nucleation-propagation model,
nucleation condensation model, stepwise sequential and hierarchical folding
model, framework model, modular model, diffusion-collision model, hydrophobic
collapse model, jigsaw puzzle model and folding funnel model. Currently,
folding funnel model has replaced all other models of protein folding. The
folding funnel model is represented in terms of energy landscape and describes
both thermodynamic and kinetic aspects of the transformation of an ensemble of
unfolded protein molecules to a predominantly native state. Various types of
interactions are involved in protein folding including hydrophobic interaction,
hydrogen bonding, van der Waal¡¯s interaction and electrostatic interactions.
Research has shown that main chain hydrogen bond plays a keyrole in protein
unfolding and folding[4-6]. This is supported by the findings that
hydrogen bond plays an important role in unfolding of ¦Â-catenin[7].
Traditionally, disruption of hydrophobic interactions instead of hydrogen bonds
has been thought to be the most important cause of protein denaturation.
The
competition between productive folding and aggregation is a fundamental feature
of folding in cells. When proteins misfold specialized proteins known as
molecular chaperones assist in the refolding of misfolded proteins and if protein
still persists in misfolded state it is subjected to proteasomal degradation
for the maintenance of cell homeostasis. Despite of cellular protein quality
control, proteins often misfold in the cell. This occurs because of
dominant-negative mutations, from changes in environmental conditions (pH,
temperature, protein concentration), error in posttranslational modifications,
increase in the rate of degradation, error in trafficking, loss of binding
partners and oxidative damage. All of these factors can act either
independently of each other or simultaneously[8]. Misfolded proteins
are associated with many diseases (Table 1). A number of in vitro and in vivo
experiments have lead to the conclusion that especially partially unfolded or
misfolded intermediates are prone to aggregation, in particular at high peptide
concentrations[9-13]. Besides this, natural mutations that decrease
the net charge or increase the hydrophobicity and ¦Â-sheet propensity of a polypeptide
chain can also result in the formation of partially misfolded intermediates.
Such partially unfolded/misfolded intermediates are populated under denaturing
conditions. Contrary to this belief, recent studies have shown that
denaturation of IDP Osteopontin (OPN), lead to formation of extended, random
coil-like conformation and stable, cooperatively many folded conformation[14].Further,
these IDPs are associated with human diseases, including cancer, cardiovascular
disease, amyloidoses, neurodegenerative diseases, and diabetes. According to
Uversky hypothesis: interconnections among intrinsic disorder, cell signaling,
and human diseases suggest that protein conformational diseases may occur not
only from protein misfolding, but also from misidentification, missignaling,
and unnatural or nonnative folding. Thus, reducing the capability to recognize
proper binding partners thereby leading to the formation of aggregate[15].
The
intermediate including partially misfolded intermediates aggregate by
interacting with complementary intermediate through exposed hydrophobic
residues and form oligomers and consequently, protofibrils and fibrils. These
intermediates do not cross polymerize or aggregate. These amyloid fibrils
accumulate as amyloid deposits in the brain and central nervous system in
Alzheimer's disease (AD), Prion disease, Parkinson's disease (PD) and Amylo
lateral Sclerosis (ALS). Amyloid-like fibrils display many common features
including a core cross-¦Â-sheet structure in which continuous ¦Â-sheets are
formed with ¦Â-strands running perpendicular to the long axis of the fibrils[16].
These amyloid fibrils typically consist of 2-6 unbranched protofilaments of 2-5
nm in diameter which are associated laterally or twisted together to form
fibrils of 4-13 nm diameter[17-19]. These fibrillar aggregates bind
dyes such as congo red and thioflavin-T and give rise to birefringence and
fluorescence respectively.
Recently,
Sambashivan and colleagues[20] have proposed that fibrils contain
native-like structure possessing biological activity based on the model of
domain-swapped functional units of RNase. These fibrils contained native like
carboxy-terminal ¦Â-strand and core
domain. The spine of the fibril exists as twisted pair of interdigitated,
antiparallel ¦Â-sheets formed by
the Q10 insertions, suggesting that protein refolding is not required to create
fibrils. In a similar vein, it was shown that at physiological pH, human
pancreatitis-associated protein form fibrillar aggregates that contained
native-like structure[21] unlike fibrillar species which adopt
cross-beta sheet structure. For transthyretin (TTR) the solvent accessibility
of the fibrils were compared with the native TTR crystal structure and the
result showed that TTR fibrils retained native-like structure[22].Thus,
these studies suggest that amyloid-beta fibrils often possess native like
structure. Until the end of 1990s, studies have shown that the amyloid fibrils
were the main toxic species in amyloid plaques. These findings were not
validated until then. However, at the end of the 1990s the attention shifted to
the cytotoxicity of amyloid fibril precursor: amyloid oligomers[23].
This was confirmed by the severity of cognitive impairment in Alzheimer's
disease which appears to better correlate with the levels of oligomeric species
of A¦Â rather than with the amount of fibrillar deposits[24].
Therefore, amyloid oligomers are now considered as important key players of
amyloid cytotoxicity. Later on, more amyloid oligomers were discovered and were
implicated in the neurodegenerative diseases thus supporting amyloid oligomer
as main culprit behind toxicity[25]. Keeping above views in mind, in
this review current knowledge of protein folding including various folding
models and protein folding in the cell have been discussed. Moreover, the
mechanism of amyloid fibril formation and mechanisms of A¦Â oligomer mediated
toxicities have also been discussed.
PROTEIN
FOLDING MODELS
Several different folding models arising from theoretical
considerations[26], folding simulations, or experimental
observations[27], have been proposed to overcome Levinthal paradox.
Among them, classical nucleation-propagation model suggests that helix-coil
transition involves nucleation step followed by a rapid propagation, the
limiting step being the nucleation process. More recently, a nucleation
condensation model, different from the classical one, has been proposed by
Fersht[28]. According to this model, weak local nucleus are formed
which is stabilized by long range interactions. The stepwise sequential and
hierarchical folding model suggests that several stretches of secondary
structures are formed and assemble at different levels following a unique route[27,29].
In this model, the first event is nucleation consequently the secondary
structures are formed that associate to generate supersecondary structures,
then domains and eventually monomer. The framework model assumes that the
secondary structure is formed in an early step of folding, followed by the
formation of tertiary structure, emphasizing the role of short range
interactions in directing the folding process[30]. A modular model
of folding was proposed based on the three-dimensional structures of proteins.
This model assumes that not only domains, but also subdomains can serve as
folding units which fold independently of each other forming structural modules
that assemble to yield the native protein[31,32]. The
diffusion-collision model of folding[33] suggests nucleation occurs
simultaneously in different regions of the polypeptide chain generating
microstructures which diffuse, associate and coalesce to form substructures
with a native-like conformation that eventually give rise the native protein
structure. The hydrophobic collapse model implies that in the first step,
polypeptide chain collapses via long range hydrophobic interactions followed by
the formation of secondary structure and consequently tertiary structure.
Later, Dill and co-workers proposed that stretches of secondary structures are
formed simultaneously with the hydrophobic collapse and consequently native
protein structure is formed[34]. The jigsaw puzzle model was
introduced in 1985 by Harrison and Durbin[35]. This model supports
the existence of multiple folding routes to reach a single native state.
DETECTION AND
CHARACTERIZATION OF INTERMEDIATES IN PROTEIN FOLDING
The unfolding-refolding transition under equilibrium has often been
treated as a two-state mechanism. This implies that transition of the native to
the denatured state is an ¡°all-or- none¡± process that involves only two
conformational states, the native and denatured states which are significantly
populated. Further, if at all any intermediate state exists; it exists
transiently and poorly populated under equilibrium conditions. However,
existence of intermediates has been shown from kinetic studies for most
proteins even for proteins showing two-state mechanism. These experimental
evidences prove the occurrence of intermediates in the folding pathway. The
structural characterization of such intermediates is a prerequisite to solving
the folding problem. Two major obstacles are encountered in characterizing
these species: high cooperativity of the transition and rapidity of the
process, especially in the early steps of protein folding. Nevertheless, using
improved methods it is possible to detect intermediates, for instance during
the refolding of disulfide-bridged proteins like lysozyme[36] and
bovine pancreatic trypsin inhibitor (BPTI)[37,38]. An elegant method
using differential chemical labeling has been elaborated by Gh¨¦lis[39]
and applied to the refolding of elastase. In the past decades, substantial
technological advances have been made to characterize intermediates,
particularly by stopped-flow mixing devices coupled to circular dichroism, and
NMR using rapid hydrogen-deuterium exchange associated with a mixing system
allowing for the pulse labeling of transient species. This method is highly
informative, yielding residue-specific information[40-42]. Classical
rapid mixing techniques such as stopped-flow, continuous flow and quenched-flow
are limited to the millisecond time scale, thus preventing analysis of the
early events occurring within the initial burst phase of protein folding. In
spite of this, recently technical advances in kinetic studies have been made in
characterizing these intermediate[43]. For example, sub millisecond
mixing techniques have been developed for studying the early steps of folding
of cytochrome c.
Studies have
shown that protein folding involves three common stages:
1. Initially, the unfolded protein collapses to more compact state
containing substantial nonpolar surfaces and secondary structure. This species
has little thermodynamic stability and encompasses an ensemble of conformations
which are in dynamic equilibrium and may contain non-native structure. This
stage occurs in less than 5 ms and, transition maybe noncooperative in nature.
2. The next
phase involves further development of secondary and the beginnings of specific
tertiary structure throughout the protein molecule showing measurable
stability. In this step, subdomains are formed that are yet to be properly
docked..Further, in these intermediate steps, substrate or ligand-binding sites
are formed in protein molecules. For example, in -lactalbumin, Ca2+-binding
sites appear before completion of the native structure[44]. The
packing is not as tight as is ultimately found in the native conformation,
suggesting that the side chains are in general more mobile This stage, which
may consist of more than single kinetic step and occurs in the 5-1,000 ms time
range.
3. In the
final steps of protein folding, precise ordering of the elements of secondary
structure, the correct packing of the hydrophobic core, the correct domain
pairing in multidomain proteins, the reshuffling of disulfide bonds, cis-trans
proline isomerization occur before the formation of the native structure.
MOLTEN-GLOBULE,
PRE-MOLTEN GLOBULE AND DRY-MOLTEN GLOBULE INTERMEDIATES
Kinetic refolding experiments in vitro as well as theoretical
calculations suggest that protein folding is a sequential hierarchical process[45],
with the existence of early stable species with a high content of secondary
structures. These secondary structures were coined as molten globule by Ohgushi
and Wada[46]. The characteristic features of the ¡®molten globule¡¯
state are: (i) It contains extensive secondary structure; (ii) It has loose
tertiary contacts without tight side-chain packing; (iii) It is less compact
than the native state; (iv) It is more compact than the unfolded state[47];
(v) It contains an accessible hydrophobic surface which binds hydrophobic dye
aniline naphthalene sulfonate. Since the tertiary structure is not stabilized,
therefore near UV-CD spectra is not detected. The formation of a molten globule
as an early folding intermediate has been reported for several proteins
including -lactalbumin,
carbonic anhydrase, ß-lactamase, and the - and ß2-
subunits of tryptophan synthase, bovine growth hormone, and phosphoglycerate
kinase[48-50].
An
intermediate state has been identified that precedes the molten globule state[49,51].
This species is less compact than a molten globule, contains significant amount
of secondary structure contents which are smaller than that of a molten
globule, and displays hydrophobic regions accessible to a solvent. This
intermediate state has been called a pre-molten globule by Jeng and Englander[52]
and has been observed during the cold denaturation of ß-lactamase, carbonic
anhydrase, and also during the refolding of several proteins[53].
Since these transient intermediate states are formed within the dead-time of a
stopped flow device. Thus, it is possible that their formation might be
preceded by an earlier folding step.
Recently, dry
molten globule intermediates have been discovered, which exists in expanded
state lacking appreciable solvent in which side chains unlock and gain
conformational entropy, while liquid-like van der Waals interactions persist.
The dry molten globule does not bind hydrophobic dye aniline naphthalene
sulfonate. Currently, research has shown that four different proteins form dry
molten globules as the first step of unfolding, suggesting that such an
intermediate may be commonplace in both folding and unfolding[54].
Discovery of dry molten globule intermediates has major implications for future
experimental work on the mechanism of protein folding.
THE ENERGY
LANDSCAPE AND THE FOLDING FUNNEL
MODEL
The folding funnel model has evolved from both experiment and theory
through the use of simplified mechanical models that benefit from the concept
of folding funnel introduced by Wolynes and co-workers[55]. The
model is represented in terms of an energy landscape and describes both
thermodynamic and kinetic aspects of the protein folding. A folding funnel is a
simplified 2D representation of the very high-dimensional conformational space
that is accessible to the polypeptide backbone during folding[56].
The broad top of funnel shows vast number of conformations present in the
soluble denatured state, the narrow bottom of the funnel represents the unique
native structure of the protein. The separation between the top and bottom of
the funnel represents other energy contributions (chain enthalpy, solvent
entropy and enthalpy) to each chain conformation. Starting from the ensemble of
unfolded conformations the folding funnel allows several pathways that proceed
to the global free energy minimum corresponding to the native structure. As the
chain folds to lower energy conformations, it might also populate intermediate
states along the sides of the funnel. These kinetic traps might hinder and/or
promote the formation of the native structure depending on their depth, the
barriers between the trap and the native conformation, and the rest of the
funnel surface. According to the statistical mechanics, the number and depth of
local kinetic traps on the funnel landscape represent the degree of frustration
of the polypeptide sequence[57]. Current folding funnels cannot,
however, account the behavior of most polypeptide chains under physiological
conditions. Although the model starts with all possible initial conformations
at the top of the funnel, they describe the folding behavior of only single
polypeptide chain at infinite dilution. They do not consider intermolecular
collisions between partially folded chains which is intrinsic feature of actual
folding processes leading to
self-association. Because misfolding is often associated with self-association,
polymerization or aggregation, the funnel models cannot account for the
aggregation behavior of many proteins[58,59]. However, in folding
funnel diagrams, an off-pathway aggregation reaction can be incorporated as second
¡®aggregation¡¯ funnel[60]. Like intramolecular folding, in
aggregation the association of two or more non-native protein molecules is
largely driven by hydrophobic forces and primarily results in the formation of
amorphous structures (Figure 1)[61]. Alternatively, aggregation can
lead to the formation of highly ordered, fibrillar aggregates called amyloid
(Figure 1).
These results
are restricted to a subset of proteins under physiological conditions. Thus,
energy landscape metaphor provides a conceptual framework for understanding
two-state and multistate kinetics, misfolding and aggregation process. Energy
landscape ideas also have allowed successful development of protein structure
prediction algorithms[62].
PROTEIN
FOLDING IN the CELL
The main rules that govern protein folding have been mainly deduced
from in vitro studies. The in vitro refolding is considered as a good model to
understand the mechanisms by which a nascent polypeptide chain acquires the
three dimensional structure in the cell. However, the intracellular environment
is highly crowded containing about 300-400 mg/mL of macromolecules[63]
which differs markedly from that of the test tube where low protein
concentrations are used for carrying out protein folding-unfolding transition.
Under these in vitro and in vivo conditions, do the same mechanisms account for
protein folding? This question has been particularly challenged by the
discovery of molecular chaperones in 1987. These molecular chaperones are
nanomachines that catalytically unfold misfolded and alternatively folded
proteins[64]. Molecular chaperones and their associated
co-chaperones are essential in health and disease as they are key facilitators
of protein folding, quality control and function. The HSP70 and its co-chaperones
have been recognized as potent modulators of inclusion formation and cell
survival in cellular and animal models of neurodegenerative disease. Now, it
has also become evident that the HSP70 chaperone machine functions not only in
folding, but also in proteasome mediated degradation of neurodegenerative
disease Thus, there has been a great deal of interest in the potential
manipulation of molecular chaperones as a therapeutic approach for many
neurodegenerations. Most recently, mutations in several HSP70 co-chaperones and
putative co-chaperones have been identified as causing inherited
neurodegenerative and cardiac disorders, directly linking the HSP70 chaperone
system to human disease[65]. The molecular chaperones GroEL/GroES
also accelerate the refolding of a multidomain protein by modulating on-pathway
intermediates[66]. Now more than 20 protein families have been
identified as molecular chaperones, the heat-shock protein Hsp 70 (Dnak in
Escherichia coli), and Hsp40 (DnaJ in E.coli) show little or no specificity for
the proteins they assist.
Molecular
chaperones assist in the folding of protein by two different mechanisms. In the
first mechanism, small chaperones bind transiently to small hydrophobic regions
of nascent polypeptide chains thereby prevent aggregation and premature
folding. This binding and release by some, but not all, small molecular
chaperones is regulated in a complex ATP-dependent pathway. Contrarily, in the
second mechanism large chaperones such as the GroEL-GroES system in prokaryotes
or TriC in eukaryotes completely sequester the non-native proteins in a central
cage. This cage is formed by the heptameric double ring of GroEL and is capped
by GroES to prevent the premature release of the folding protein. This cage is
large enough to accommodate protein molecules up to about 70kDa. The Figure 2
shows the GroEL reaction cycle[67]. Briefly, the non-native protein
binds to the apical domains of the upper ring of GroEL-GroES. Consequently, ATP
and GroES bind to the ring and sequester the protein. The binding of GroES
induces a large conformational change in GroEL and ATP hydrolysis induces a
conformational change in the bottom ring allowing it to bind a misfolded
protein. This promotes subsequent binding of ATP and GroES in the lower ring,
disrupting the upper complex and ejecting GroES and releasing the protein. If
the protein does not attain the native state, it is subjected to a new cycle.
The hydrolysis is required in some cases for the release of the protein.
Thus,
molecular chaperones transiently associate with nascent misfolded proteins;
therefore play an important role in preventing improper folding and
aggregation. Infact they do not interact with native proteins. They bind
non-native proteins through hydrophobic interactions. They do not carry code
for directing a protein to adopt a structure different from that dictated by
the amino acid sequence. Therefore, the role of molecular chaperones is to
assist protein folding in vivo without violating the Anfinsen¡¯s postulate. They
also increase the yield but not the rate of folding reactions; which implies
they do not act as catalysts.
Other
accessory molecules also play a helper role in the folding of proteins in vivo.
For instance, protein disulfide isomerase, an abundant component of the lumen
of the endoplasmic reticulum, catalyzes the formation of disulfide bonds in
secretory proteins thereby accelerate the folding process. Another enzyme,
peptidyl-prolyl-cis-trans isomerase, catalyzes the cis-trans isomerization of
X-Pro peptide bonds. Consequently, it accelerate the folding process.
PROTEIN
MISFOLDING, AGGREGATION AND AMYLOID FIBRIL FORMATION
In protein misfolding, protein molecule is converted into non-native
state. These misfolded proteins are kinetically trapped in local energy minima.
Misfolding generally occurs due to dominant-negative mutations, from changes in
environmental conditions (pH temperature, protein concentration), error in
posttranslational modifications (phosphorylation, advanced glycation,
deamidation, etc.), increase in the rate of degradation, error in trafficking,
loss of binding partners and oxidative damage[68]. These factors can
act either independently of each other or simultaneously[8].
Misfolded protein or partially folded intermediates have large patches of
contiguous surface hydrophobicity and therefore aggregate more readily than
native and unfolded state which have hydrophobic amino acid located at the
interior core of protein and lie scattered in the polypeptide chain
respectively. These partially misfolded intermediates aggregate by interacting
with complementary intermediate and consequently give rise to the formation of
oligomers thereby proto-fibrils and fibrils. These proteinaceous fibril seeds
can therefore serve as self-propagating agents for the instigation and
progression of disease. The alzheimer¡¯s disease and other cerebral proteopathies
seem to arise from the de novo misfolding and sustained corruption of
endogenous proteins, whereas prion diseases can also be infectious in origin[69].
Recently, several independent lines of studies on different proteins
indicate that oligomers might be the most toxic species in the misfolding and
aggregation pathway[70-72]. This is validated by the findings that
early aggregate of A¦Â peptides, ¦Á synuclein[73], transthyretin[74]
lead to the formation of AD, PD and ALS disease[75,76,73]. Lack of a
direct correlation between the fibrillar plaque density and the severity of the
clinical symptoms in patients suffering with AD or PD further justify that
early aggregates are more toxic entities[77]. Furthermore, when
transgenic mouse models were exposed to early aggregates disease-like
phenotypes appeared in these mouse[78].
Both amyloid
oligomers and fibrils are formed via a variety of pathways including reversible
association of native monomers, aggregation of conformationally altered
monomer, aggregation of chemically modified product, nucleation-elongation
polymerization and surface induced aggregation[79].Thus giving rise
to diverse fibril structures or polymorphism[80]. Additional
polymorphisms arise when the same polypeptide chain occurs in a range of
structurally different morphologies[79]. Among these fibrillation
pathways, nucleation-elongation polymerization is generally more accepted
(Figure 3).
Therefore in
the following passage only this mechanism has been discussed.Briefly, in this
mechanism the reaction rate depends on the protein concentration and can be
accelerated by the addition of homologous pre-aggregated proteins[81-86].
The amyloid aggregation occurs in three consecutive stages: (1) The first stage
is thermodynamically disfavored and is known as lag phase where the soluble
monomers associate to form nuclei; (2) The second step is exponential phases in
which population of these transient nuclei species triggers the polymerization
and fibril growth; (3) The third stage is saturation phase in which essentially
all soluble species are converted into mature fibrils by associating laterally[84,87].
The
nucleation-elongation aggregation reaction was first described by Oosawa and
Asakura[88]. According to this model, the lag phase nuclei are in a
very unfavorable thermodynamic equilibrium with native monomeric species[89].
In nucleation-elongation aggregation reaction, the fibril mass is proportional
to the square of the elapsed time consequently no lag phase exists. But
actually the scenario is much more complex because nucleation step is catalyzed
by pre-existing aggregates. Thus, from these pre-existing aggregates initial
nuclei are formed, leading to the formation of critical number of aggregates
and secondary nucleation pathway.
The second
phase is a growth phase which consists of several steps and is
thermodynamically driven[84,87]. In the first step of growth phase, -sheet oligomers
are converted into non-fibrillar -sheet assemblies or these
oligomers are converted into large amorphous aggregates, which undergo
structural rearrangement, first, to nonfibrillar -sheet assemblies
and finally to fibrils. In the last step, mature fibrils are formed usually by
lateral association.
Formation of
amyloid oligomers and fibril are significantly affected by macromolecular
crowding. The major effects being those due to excluded volume and increased
viscosity. This is validated by the findings that macromolecular crowding may
lead to a dramatic acceleration in the rate of alpha-synuclein aggregation and
formation of amyloid fibrils[90].
Most recently
the structures of human brain-derived A fibrils from two
patients have been studied[91]. The structures of human brain-derived
A fibrils were
compared with the structures of in vitro A fibrils. Results
have shown novel conformational features in Ab40 fibrils from patient I, for
instance a twist in residues 19-23 occur that allows side chains of either F20
or E22 to be buried within the structure, a kink at G33 that allows side chains
of I32 and L34 to point in opposite directions and make contacts with different
sets of A40 molecules, and
a bend in glycine residues 37 and 38. Contrary to this, fibrils formed in vitro
by A40 and A42 contain
relatively simple strand-bend-strand conformations. The N-terminal is
disordered in A40 and A42 whereas A40 fibrils from patient I showed structural order in this region.
Analysis of the fibril structure
from patients I and II showed differences in both peptide backbone conformation
and interresidue interactions, but not overall symmetry. Thus, these data have
lead to conclusion that fibrils in the brain may spread from a single
nucleation site and that structural variations may correlate with variations in
AD[91].
MECHANISMS
OF A OLIGOMER MEDIATED TOXICITY AT A MOLECULAR LEVEL
The oligomeric species of A is now considered more pathogenic
than amyloid fibril. The A¦Â oligomers play an important role in the
pathogenesis of Alzheimer diseases.There are several mechanisms by which A¦Â
oligomer causes toxicity to neuron cell. For instance, increase in membrane
conductance or leakage in the presence of small globulomers to large
prefibrillar assemblies lead to toxicity to neuron cell[92,93].
Studies have shown that formation of discrete ion channels or pores in the
membrane is another mechanism that caused toxicities[94-96].
Further, changes in the ratio of cholesterol to phospholipids in the membrane
alter membrane fluidity and thereby favor aggregation of A The presence of
rafts on the membrane may also influence aggregation of A[97]. Thus, these
data along with other reports have lead to ¡°channel hypothesis¡±; implicating
amyloid peptide channels are involved in ion deregulation leading to the
manifestation of neurodegenerative diseases[98,99].
Once A channels are
formed on neuronal membrane, disruption of calcium and other-ion homeostasis
may take place resulting in the promotion of numerous degenerative processes,
including free radical formation[100] and phosphorylation of tau[101],
thereby accelerating neurodegeneration. The free radicals also induce membrane
disruption; consequently, unregulated calcium influx is amplified which
influences the production and processing of APP. Thus, a vicious cycle of
neurodegeneration is initiated (Figure 4)[102].
Contrary to the amyloid channel hypothesis, recent data suggest that
homogeneous solutions of amyloid oligomers increase the conductance of artificial
lipid bilayers that do not show channel-like properties. These oligomers
enhanced ion mobility across the lipid bilayer[103] by
permeabilizing membrane and this is a common mechanism of pathogenesis in
amyloid-related degenerative diseases[70,104-118]. Interestingly,
studies also suggest that membrane permeabilization caused by amyloid oligomers
is due to defects in the lipid bilayer, rather than the formation of discrete
proteinaceous pores[118]. In accordance with this observation,
Demuro et al. have demonstrated that amyloid oligomers lead to increase in Ca2+
levels, whereas equivalent concentrations of monomers or fibrils did not[108].
These amyloid oligomers disrupt the integrity of both plasma and intracellular
membranes in a channel independent[108]. Thereby they increased the
permeability of the plasma membrane and penetrate cells[119] and
disrupt intracellular membranes to cause leakage of sequestered Ca2+.
The
extracellular A oligomer also
causes toxicity to neuron cells by binding to the cell-surface
N-methyl-D-aspartate receptor (NMDAR)[120] and other receptors
resulting in synaptic dysfunction and neurodegeneration. Yamamoto and
colleagues[121] have shown that A oligomers induce nerve growth
factor (NGF) receptor-mediated neuronal death. Other reports on neuronal
receptor-mediated toxicity mechanisms suggest that A disturbs NMDAR-dependent long-term
potentiation induction both in vivo and in vitro thereby causing
neurodegeneration.Besides this, A oligomer specifically inhibits several major signaling pathways
downstream of NMDAR, including the Ca2+-dependent protein
phosphatase calcineurin, Ca2+/calmodulin-dependent protein kinase II
(CaMKII), protein phosphatase 1, and cAMP response element-binding protein
(CREB)[122].
Lastly,
because these species are foreign to host therefore they are likely to trigger
inflammatory and apoptotic responses in brain. This is supported by the
findings that oligomers and fibrils form of beta-amyloid triggers inflammatory
and apoptotic responses in human brain and alzheimer¡¯s disease mouse model[123-125].
Conclusions
Acquisition of the native three-dimensional structure
of protein is one of the most fascinating areas of molecular biotechnology and
biochemistry. Consequently, protein folding has been the subject of extensive
investigation for the last five decades. To overcome Levinthal paradox several
folding models have been discussed. Among them, folding funnel model has replaced all
existing folding models. This model is represented in terms of an energy
landscape and describes both thermodynamic and kinetic aspects of the
transformation of an ensemble of unfolded protein molecules to a predominantly
native state. According to this model, there are parallel micropathways, where
each individual polypeptide chain follows its own route. Towards the bottom of
the folding funnel, the number of protein conformations decreases as does the
chain entropy. The second funnel shows the aggregation pathway to amorphous
structure and to fibrillar state. Now oligomeic species is considered more
toxic species than fibrils. The A oligomeric
species cause toxicities by several mechanisms including neuron membrane
disruption through increase in membrane conductance or leakage in the presence
of small globulomers to large prefibrillar assemblies, direct formation of ion
channels and by binding to different cell-surface receptors. Thus, by
inhibiting these toxic pathways will possibly lead to cure of devasting AD in
future. This can be achieved by designing novel inhibitors for these toxic
pathways.
Acknowledgements
Author acknowledges the facilities of Aligarh Muslim
University, Aligarh, 202002, India.
CONFLICT OF INTERESTS
The Author has no conflicts of interest to declare.
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Peer reviewers: Raj Kumar,
Department of Basic Sciences, The Commonwealth Medical College, 525 Pine
Street, Scranton, PA-18512, USA; Gongyi Zhang, Associate Professor, Department
of Biomedical Research, National Jewish Health and Department of Immunology and
Microbiology, School of Medicine, University of Colorado Denver, USA; Leonid
Breydo, Department of Molecular Medicine, University of South Florida, Tampa,
FL 33612, USA.
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