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Published as doi: 10.1096/fj.07-099671.
 (The FASEB Journal. 2008;22:2115-2133.)
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Molecular and cellular aspects of protein misfolding and disease

Eszter Herczenik* and Martijn F. B. G. Gebbink*,{dagger},1

* Laboratory of Thrombosis and Haemostasis, Department of Clinical Chemistry and Haematology, University Medical Center Utrecht, The Netherlands; and

{dagger} Crossbeta Biosciences BV, Utrecht, The Netherlands

1Correspondence: Laboratory of Thrombosis and Haemostasis, Department of Clinical Chemistry and Haematology, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands. E-mail: m.gebbink{at}umcutrecht.nl


   ABSTRACT
TOP
 ABSTRACT
THE APPEARANCE OF PROTEINS
 PROTEIN MISFOLDING DISEASES
 MOLECULAR BASIS OF PROTEIN...
 THERAPEUTIC APPROACHES TO...
 REFERENCES
 
Proteins are essential elements for life. They are building blocks of all organisms and the operators of cellular functions. Humans produce a repertoire of at least 30,000 different proteins, each with a different role. Each protein has its own unique sequence and shape (native conformation) to fulfill its specific function. The appearance of incorrectly shaped (misfolded) proteins occurs on exposure to environmental changes. Protein misfolding and the subsequent aggregation is associated with various, often highly debilitating, diseases for which no sufficient cure is available yet. In the first part of this review we summarize the structural composition of proteins and the current knowledge of underlying forces that lead proteins to lose their native structure. In the second and third parts we describe the molecular and cellular mechanisms that are associated with protein misfolding in disease. Finally, in the last part we portray recent efforts to develop treatments for protein misfolding diseases.—Herczenik, E., and Gebbink, M. F. B. G. Molecular and cellular aspects of protein misfolding and disease.


Key Words: protein structure • aggregation • amyloid • Alzheimer’s disease • atherosclerosis • therapy


   THE APPEARANCE OF PROTEINS
TOP
 ABSTRACT
 THE APPEARANCE OF PROTEINS
PROTEIN MISFOLDING DISEASES
 MOLECULAR BASIS OF PROTEIN...
 THERAPEUTIC APPROACHES TO...
 REFERENCES
 
The structure of proteins
PROTEINS ARE MOLECULES COMPOSED OF an amino acid chain, in which each amino acid is connected to the next one by a peptide bond. Proteins are very diverse and vary in size from small peptides to large multimers. The common element of proteins is the peptide backbone formed by peptide bonds that link the amino acids. The variation among peptides is related to the sequence of the amino acids and their side groups. There are 20 different amino acids, and they have either acidic, basic, neutral, or hydrophobic side chains. The order of the amino acids determines the primary structure of the protein by creating a unique polypeptide chain, which is relatively flexible (Fig. 1 ). Polypeptides can fold into three secondary elements: the {alpha}-helix and the β-sheet, which determine the three-dimensional structure of the protein, and the random coil, which has less ordered interchain amino acid side chain interactions, leaving free rotation around each bond. The tertiary structure refers to the distribution of the {alpha}-helices and β-sheets and random coils in the protein, wherein these elements are folded into a compact conformation stabilized by hydrogen bonds or ionic interactions. The term quaternary structure is used for the description of multimeric proteins, in which the different polypeptide chains are connected.


Figure 1
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  		Figure 1. Schematic representation of the structural components of proteins. The order of the amino acids determines the primary structure of the protein, which can fold into secondary elements, {alpha}-helix, β-sheet, or random coil. The distribution of secondary elements ascertains the tertiary structure that is stabilized by hydrogen bonds or ionic interactions. Finally, the quaternary structure describes the connection of polypeptide subunits in multimeric proteins.

Protein folding
Protein folding is the process by which the newly synthesized protein molecule folds into its unique, three-dimensional structure. The primary product of protein synthesis is the linear amino acid chain, which lacks any three-dimensional structure. To become functional, the protein has to be packed into its particular native conformation. In the cell, a variety of proteins named chaperones assist the newly synthesized polypeptide to attain its native conformation. Some chaperones are highly specific in their function; others are very general and can be of assistance to most globular proteins. Protein folding is a very complex process, and identification of the molecular mechanisms responsible for protein assembly is one of the most elemental open questions in biochemistry. The energy landscape theory that was first proposed by Joseph Bryngelson and José N. Onuchic (1) states that folding of a protein does not follow a singular, specific pathway; it is in fact a rather complex self-organizing process that generally does not occur through an obligate series of intermediates but rather through routes down a folding funnel (Fig. 2 ) (2) . The energy of the different conformations decreases with the development of organized, native-like properties. On the highest energy level, proteins do not comprise ordered structures. As the proteins fold more into the native conformation and the secondary structural arrangements appear at certain positions of the polypeptide chain, they shift to a lower energy phase. At the end of the correct folding procedure, as the proteins obtain their correctly packed native conformations with a unique set of {alpha}-helical and β-sheet motifs, they find their energy minimum. The drive for the energy minimum makes the correct protein folding highly efficient and very rapid. Thermodynamically, the folding process is described as an energy funnel (3) (Fig. 2) , wherein the unfolded states are characterized by a higher degree of conformational entropy (S) and free energy (G) than the native state (4) . The facade of this folding funnel is unique for a specific polypeptide sequence under a particular set of conditions. By definition, entropy is a measure of chaos, the amount of all different conformational states that the protein can attain. Free energy stands for the amount of thermodynamic energy in a system that can be converted into work. The unfolded state is associated with more chaos, higher entropy, and free energy, which leads to the unstableness of the three-dimensional structure. Therefore, as folding proceeds, the narrowing of the funnel represents a decreased number of conformational states as well as lower free energy (Fig. 2) . At the bottom of the funnel, which is also known as the global minimum, the folding alternatives are reduced to a single conformation. Although the free energy funnel is described with one global minimum, which corresponds to the native conformation, a protein can have a whole set of different native conformations, which are important for fulfilling its biological function. The very rapid and efficient search for the native state is encoded by a network of interactions between "key residues" in the structure, forming a folding nucleus that establishes the native topology in the transition state ensemble (the folding transition bottleneck) (5) .


Figure 2
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  		Figure 2. Energy state of protein folding under physiological and misfolding conditions. The shape of the graph shows energy state of the protein conformations moving toward its native or misfolded condition through multiple inter- and intramolecular contact arrangements.

Protein misfolding: aggregation and amyloid formation
Protein misfolding is a common and intrinsic propensity of proteins that occurs continuously. Misfolding is influenced by the amino acid composition, and certain mutations are known to accelerate the process. Moreover, it also depends on environmental conditions, because once proteins are exposed to specific environmental changes such as increased temperature, high or low pH, agitation, elevated glucose, or oxidative agents (Table 1 ), they can lose their native conformation more rapidly. The process wherein the native state is disrupted is called denaturation, and it generally results in the unfolding of the proteins. Because of the lack of arrangement, unfolded proteins are nonfunctional. Importantly, the unfolded state is thermodynamically unfavorable and unstable (Fig. 2) . Seeking lower energy levels and more stability, unfolded proteins have a tendency to aggregate.


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  		Table 1. Summary of protein-modifying conditions and their affected proteins or peptides

Subsequent to protein unfolding, aggregation, which consists of two parts, starts. The first part is the nucleation, when proteins reversibly attach to a growing core. When the nucleus crosses the threshold of a critical mass, the second part begins, wherein further protein molecules attach irreversibly to the core, developing a large aggregate. Studies with small fiber-forming peptides have shown that during aggregation, the free energy change depends on the concentration of monomer. At low concentrations the monomeric state is favored and at high concentrations the aggregated state is favored because of the large barrier that needs to be overcome to resolve the aggregates (6) , which makes the aggregate highly stable. The aggregation procedure is thought to be initiated by protein segments with hydrophobic amino acid residues, β-sheet predisposition, and low net charge (7) . These segments are the precursor cores, which can facilitate further aggregation. Depending on the protein, there are various alternatives concerning how the precursor is generated from native proteins. These are incomplete or incorrect proteolysis (8) or introduction of a misfolded variant (9 , 10) that undergoes partial misfolding introducing a precursor pool from which they rapidly aggregate (11) . Protein aggregation can result in various different structural appearances with intermediates (oligomers) varying from unordered amorphous aggregates to highly ordered fibrils that are called amyloid (Fig. 3 ). They are generally enriched in cross-β structure (12) , yet fluctuate in sequence, time, and conditions (13) .


Figure 3
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  		Figure 3. Protein misfolding and aggregation. Under certain circumstances such as pH or temperature change, mechanical stress, glycation, or oxidation, proteins undergo conformational changes that result in unfolding and partial misfolding that is associated with the tendency to aggregate. During aggregation, proteins can obtain a range of different structural appearances, which are generally enriched in cross-β structure, including intermediates varying from unordered amorphous aggregates to ordered fibrils that are called amyloid.

One specific form of the aggregated proteins is amyloid conformation, which is very stable, but its formation can still be reversible (14) . Amyloid consists of linear, unbranched protein or peptide fibrils. Contrary to the well-known fibrillar proteins such as collagen triple helix or keratin helices, amyloid is exceptional among other, naturally occurring biological fibrils (15) . The amyloid fibrils bind the fluorescent probes Congo red and thioflavin derivatives (16 , 17) , and they share a common secondary composition, the cross-β structure (18) . The cross-β structure was initially identified by X-ray analysis, which demonstrated a strict arrangement, in which the β-strand direction is perpendicular to the fibril axis (Fig. 4 ) (19 , 20) . However, recent progress in biophysical techniques allows researchers to gain a more detailed view of fibril structure, and it is becoming more obvious that there are no universal tertiary and quaternary structures for amyloid fibrils (18) . They can attain either parallel (21 , 22) or antiparallel β-sheet conformation (Fig. 4B ) (23 , 24) and other structural elements (18) .


Figure 4
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  		Figure 4. Composition of amyloid cross-β structure. A) Proteins with amyloid cross-β structure are characterized by 4.7-Å interstrand and ~10-Å intersheet space. B) The arrangement of two β-strands can be antiparallel or parallel, depending on their relative direction. C) On the basis of the position of the β-strands (antiparallel or parallel) and β-sheets (face-to-face or face-to-back and up-up or up-down), there are eight structural categories of amyloid proteins. Two represent amyloid-β protein conformations, whereas tau, insulin, and prion have one single structural appearance.

Thus, besides their common characteristics, amyloids present conformational plasticity, the ability to adopt more than one stable tertiary fold that accounts for conformational differences within fibrils formed by one single polypeptide. These structural variations raise the question of the precise composition of the cross-β structure. The work of David Eisenberg and colleagues offers answers to fundamental questions concerning the structural characteristics for amyloid proteins (25) . Using X-ray microcrystallography, they investigated small peptides that developed both microcrystals and fibrils, which consisted of a pair of β-sheets and each sheet was formed by β-strands. One β-strand corresponds to a single peptide, and these β-strand peptides compose β-sheets with a close "dry" interface, which is therefore termed a steric zipper. These steric zippers (β-sheet pairs) repeat all along the entire needle-shaped crystals. Eisenberg extended his observations to the structure of various amyloid proteins and found divergence between the basic arrangements of steric zippers in amyloid fibrils. He categorized the amyloid proteins into eight classes, depending on three structural principles: first, whether their β-strands were antiparallel or parallel; second, whether the β-sheets were packed "face-to-face" or "face-to-back"; and third, whether the orientation of the β-sheets was "up-up" or "up-down" with respect to each other (Fig. 4C ) (26) . Most of the eight variations of steric zippers that were described have been observed in amyloid proteins such as tau, prion, amyloid-β, and insulin, which are associated with protein misfolding diseases.


   PROTEIN MISFOLDING DISEASES
TOP
 ABSTRACT
 THE APPEARANCE OF PROTEINS
 PROTEIN MISFOLDING DISEASES
MOLECULAR BASIS OF PROTEIN...
 THERAPEUTIC APPROACHES TO...
 REFERENCES
 
Protein misfolding diseases represent a group of disorders that have protein aggregation and plaque formation in common. Here, we provide an overview of the current understanding of protein misfolding diseases by describing the most studied diseases of the main categories (Table 2 ) and illustrating the common mechanisms of protein misfolding in protein misfolding diseases.


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  		Table 2. Summary of protein misfolding diseases and the related proteins and peptides in human.

Amyloidosis
Amyloidosis is a group of protein misfolding diseases, in which protein aggregates accumulate either systemically or locally in certain organs or tissues (Table 2) . Amyloidosis can be either hereditary or acquired (52) . The hereditary forms are caused by mutations in the genes of (mostly) plasma proteins. Little is known about the precise conditions that lead to the development of the other, acquired, forms. In patients with amyloidosis, various symptoms can arise, depending on which protein is involved and at what site the aggregation occurs. Most patients have gastrointestinal abnormalities, kidney insufficiencies, or heart problems, and the affected organs are characteristically enlarged, rubbery, and firm.

The most common form of amyloidosis is primary systemic amyloidosis, in which immunoglobulin light chains or fragments thereof that are produced by plasma cell clones form amyloid. The disease typically develops in individuals after the age of 40 and can affect both genders. The amyloid deposits occur in basically all organs of the body, inducing various complications including congestive cardiac and renal failure; hepatosplenomegaly, neuropathy, and skin lesions (53) . The diagnosis of the disorder is rather difficult; it requires histological analysis, definition of the correct amyloidosis, and characterization of the underlying plasma cell clone (54) . Unfortunately, efficient therapy is not available for most forms of amyloidosis. The aim of current treatment is to reduce the supply of the monoclonal light chain through suppression of the underlying plasma clone by autologous stem cell transplantation and chemotherapy. This is an aspecific approach with high potential risk (55) .

Alzheimer’s disease
Neurodegenerative diseases were the first described protein misfolding diseases. Alzheimer’s disease is one of the most studied conformational diseases. The small, 40- to 42-amino acid long (39- and 43-aa peptides have also been described) amyloid-β peptide aggregates accumulate and form senile plaques in the brain of patients with Alzheimer’s disease. Amyloid-β is cleaved off from its amyloid precursor protein (APP) by β- and {gamma}-secretases (Fig. 5 ). When the cleavage occurs in the endoplasmatic reticulum, the {gamma}-secretase generates 42-aa Aβ1–42. However, if it takes place in the trans-Golgi network, a shorter 40-aa Aβ1–40 is formed. APP is expressed on a wide variety of cell types including neurons, leukocytes, platelets, and epithelial cells. APP homologs have been described in evolutionarily distant organisms such as Caenorhabditis elegans and Drosophila melanogaster. APP contains a Kunitz-type protease inhibitor (56) , and the soluble form of APP is found to be a growth factor-like molecule for the proliferation of neuronal stem cells (57) , epithelial cells (58) , and keratinocytes (59) . Although Alzheimer’s disease has been one of the disorders to be recognized as a misfolding disease, with its structural and functional commonalities, such as cross-β structure formation, the possibility that there is a native amyloid-β conformation that might be different from the several misfolded forms known to be possible cannot be excluded. Unlike APP, whether amyloid-β has any physiological functions that are not associated with the disease is unclear. However, it has recently been reported that amyloid-β is involved in lipid metabolism by down-regulating sphingolipid and cholesterol synthesis (60) . Furthermore, there is disagreement about the pathology of amyloid-β. According to the amyloid cascade hypothesis (ACH), which was first introduced by John Hardy and David Allsop in 1991, the cleaved and unstable amyloid-β peptide starts to aggregate into large protein assemblies, which subsequently deposit into plaques in the brain and these large aggregates cause neurotoxicity (61) (for further references, see Molecular Basis of Protein Misfolding Diseases). However, it has been noted that the soluble oligomers, which are the intermediate products of the fibril formation process, are actually more harmful for neuronal cells than the fibrillar end products (62) (the molecular basis and cellular mechanisms for cytotoxicity will be further discussed in Molecular Basis of Protein Misfolding Diseases).


Figure 5
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  		Figure 5. Cleavage of APP by secretases results in release of soluble APP and amyloid-β.

Vascular inflammation and atherosclerosis
Vascular inflammation
Inflammation is a vascular response to cellular damage, infection, or other harmful irritations. Inflammation can be acute and chronic. The acute form is a crucial defense mechanism, which occurs at the sites of infection, physical irritation, and tissue necrosis. As the first step of the battle, leukocytes, monocytes, and neutrophils are mobilized from the blood. Monocytes transmigrate through the endothelial line into the endangered area though a cascade of adhesion molecules (63) . This process is directed by the endothelial cells, which follow a strictly timed expression of molecules. The first step is the expression of early adhesion molecules such as selectins (E-selectin), which initiate the rolling of the monocytes on the surface of the endothelial cells. The second step is the exposure of intercellular adhesion molecules (ICAMs) and vascular cell adhesion molecules (VCAMs) by the endothelial cells. ICAMs and VCAMs support stronger cell-cell interactions and adhesion by binding their counter-receptors on monocytes. Finally, a rapid transmigration of the blood cells takes place through the intercellular endothelial junctions. Chronic inflammation shares similar processes with the acute form, featuring monocyte/macrophage, lymphocyte, and plasma cell infiltration, but its duration is prolonged to weeks or years or even indefinitely (64) .

Atherosclerosis
Atherosclerosis is a disease of the vasculature that is characterized by chronic inflammation and thickening of the intima layer of arteries. Atherosclerosis can start early, even before age 20. Its progress is enhanced in some individuals and lasts throughout life (64) . High cholesterol levels and blood pressure, smoking, diabetes mellitus, and mutations in genes related to depositions in the vessel wall matrix, cytokines, and lipid metabolism are risk factors for atherosclerosis (65) .

The site of atherosclerosis is the atherosclerotic plaque, which manifests as the thickening of the arterial wall. It contains fat, cholesterol, calcium, lipoproteins, and cells such as macrophages (foam cells) derived from the blood. In the very first step of the disease, cells start to express adhesion molecules (E-selectin, ICAM, and VCAM) and cytokines in the same manner as in acute inflammation. The consequence of the prolonged vascular inflammation is that the plaque expands while the vessel wall loses its elasticity and it narrows the bloodstream (stenosis), blocking the blood supply to the tissues. The unpredictable, sudden disruption (rupture or erosion/fissure) of an atherosclerotic plaque and release of its contents to blood leads to platelet activation and thrombus formation, which is called atherothrombosis.

Recently, it has been reported that up to 60% of the atherosclerotic lesions contain fibrillar proteins (66) . Of the proteins known to misfold in vivo, several members of the apolipoprotein (Apo) family (Apo-B100, ApoA-I, ApoA-II, ApoE, and serum amyloid A) as well as amyloid-β and {alpha}1-antitrypsin are present in atherosclerotic lesions (67) . Low-density lipoprotein oxidation in plasma and in the arterial wall is a key event that leads to the formation of atherosclerotic lesions. Following its uptake mediated by scavenger receptors, oxidized low-density lipoprotein (LDL) induces foam cell formation from macrophages and triggers an array of proatherogenic events (68) . Protein modifications such as oxidation or glycation induce protein misfolding (Table 1) . The deposition of misfolded proteins in the arterial wall may contribute to reduced elasticity of the blood vessels and the initiation of vascular inflammation and atherosclerosis (67) .

The current treatment of atherosclerosis involves thrombin inhibitors (69) and cholesterol-lowering medication, for instance, statins (70) . Side effects of use of statins are liver damage (71) and muscle complications (72) . Because platelets play a critical role in the thrombotic events of atherosclerosis after plaque rupture, antiplatelet therapy (73) gains special importance.

Platelet activation
Platelets are prominent components of the thrombi that occlude arteries. Platelets are present in blood, and their role is to arrest bleeding from wounds. Platelet aggregation is initiated by agonists [thrombin, collagen, ADP, adrenalin, thromboxane (Tx) A2, serotonin, and vasopressin] and has three subsequent phases: shape change, aggregation, and degranulation (74) . In the resting state, their shape is discoid, and on activation they become spiny spheres with pseudopods. Platelet shape change results from a rapid reorganization of the cytoskeleton (75) . The storage granule membranes fuse with the plasma membrane, resulting in the release of their content to the blood. The release of dense-granule ADP and the secretion of generated TxA2 results in interaction with platelet surface receptors, ending up with a positive feedback mechanism. The ultimate result of platelet aggregation is the opening of the glycoprotein (GP) IIbIIIa ({alpha}IIbβIII) receptors on their surface. Fibrinogen can then bind to its receptor and form bridges between adjacent platelets, leading to the formation of a platelet plug (76) . The activation of the platelets plays a central role in arterial thrombosis.

In disorders that are associated with protein misfolding, platelet activation is observed. In Alzheimer’s disease, elevated levels of the platelet activation marker TxB2 were detected (77) , although the underlying mechanisms are not entirely understood. Recently, we reported that misfolded proteins can activate platelets, a process found to be mediated by scavenger receptor CD36 and agglutination receptor GPIb{alpha} (78) . Other groups described similar activation of platelets by amyloid-β (79) . Atherosclerotic plaques contain oxidized LDL, which has amyloid properties (50) and activates platelets (80) . In diabetes mellitus, high blood glucose can introduce amyloid properties in albumin (48) that might contribute to the hyperactivity of platelets in these patients (81) . Several types of systemic amyloidosis are also known to be associated with thrombosis (82 , 83) .

Interestingly, after activation with various stimuli, platelets express amyloid-β protein (84) . Amyloid-β is detected in platelet-derived microparticles in healthy subjects (85) , and the level of these microparticles is elevated in patients with atherosclerotic disease (86) and diabetes mellitus (87) . These particles are sources of tissue factor (88) , which is the prime initiator of blood coagulation. This property, together with the capacity of amyloid to activate platelets (78) , makes these particles potent triggers for combined activation of the coagulation cascade and formation of a platelet thrombus. The platelet-derived amyloid accumulates in the brain parenchyma and cerebrovasculature and may contribute to the development of Alzheimer’s disease (89) .

Links between protein misfolding diseases
A variety of diseases share the pathological feature of protein deposits, which form plaques causing altered organ function or failure (Table 2) . These protein misfolding diseases share similar pathological aspects including hypertension (90) , oxidative stress (91) , or hyperglycemia (92) , which can all result in protein misfolding (93 , 94) . The co-occurrence of unrelated symptoms with protein deposition in common supports the importance of protein misfolding in the progress of diseases. Atherosclerosis is associated with an increased risk of dementia and Alzheimer’s disease (95) and shares pathophysiological elements such as elevated cholesterol, inflammatory processes, and mutations in genes such as CD36 and ApoE (96) . Alzheimer’s disease can also develop as a secondary disorder during diabetes mellitus (97) . Secondary amyloidosis was reported to arise in patients suffering from amyloidosis (98) .


   MOLECULAR BASIS OF PROTEIN MISFOLDING DISEASES
TOP
 ABSTRACT
 THE APPEARANCE OF PROTEINS
 PROTEIN MISFOLDING DISEASES
 MOLECULAR BASIS OF PROTEIN...
THERAPEUTIC APPROACHES TO...
 REFERENCES
 
Protein misfolding diseases comprise a group of disorders that have one central aspect in common: the appearance of non-native protein structure, which is accompanied by increased aggregation and deposition of proteins. The group contains diseases with dissimilar symptoms, and the affected organs and tissues can be drastically different. In this section we describe the causes of protein misfolding diseases and attempt to summarize the mechanisms that lead to toxicity. In addition, a summary of the misfolded protein binding molecules is provided and their role is discussed.

Causative agents of protein misfolding diseases
The toxic nature of misfolded proteins is obvious, but there is disagreement about the properties of misfolded proteins that cause toxicity. The presence of protein aggregates and fibrils in patients suffering from protein misfolding diseases led researchers to the conclusion that the highly organized protein deposits are the primary cause of the pathological symptoms of the disease (133) . According to the ACH, the large fibrillar protein deposits are the main cause of neuronal damage. The in vitro observations showing that the fibrillar amyloid-β is toxic to cultured neuronal cells (134) and that it initiates membrane depolarization and action potential frequency alterations (135) and the in vivo data that demonstrate neuronal failure and microglial activation on injection of fibrillar amyloid-β preparation into the cerebral cortex of aged rhesus monkeys (136) support the ACH theory (137) .

However, recent studies suggest that prefibrillar aggregates, called micelles, protofibrils, or β-amyloid-derived diffusible ligands rather than fibrils are the most potent mediators of cell damage, cytotoxicity, and neurotoxicity. These soluble oligomers are temporally unstable, and they can rapidly transform into more mature and eventually fibrillar forms. This action is supported by the finding that the severity of cognitive impairment in protein misfolding diseases correlates with the levels of small oligomeric aggregates and not with the large fibrillar species (138 139 140 141) .

Cellular mechanisms of toxicity
Depending on the particular protein, the environment, and the conditions of precursor core generation, protein aggregation has different dynamics. It is difficult to define a general impact of the different appearances of aggregated proteins on cells. The machinery by which they disturb cellular functions is not entirely understood. The mechanisms identified that might be responsible for cellular damage are mainly initiated by the soluble, oligomeric protein aggregates, which disrupt cell membranes by inserting themselves into the phospholipid bilayer, disturbing normal ion gradients (142) ; inactivating normally folded, functional proteins, and obstructing proteasome components or chaperone proteins (143) . Oligomeric species of amyloid-β, amylin, and {alpha}-synuclein form amphiphilic, micelle-like aggregates in solution (144) and annular pores in lipid bilayers including cell membranes (145 , 146) that initiate membrane permeabilization, a common component of misfolded protein toxicity (147) . Subsequently, numerous downstream pathological events are stimulated in the cells, such as Ca2+ immobilization (148) , induction of endoplasmic reticulum stress (149) , generation of reactive oxygen species (ROS) (150 , 151) , and, finally, cell death (152) . Cell death induced by misfolded and aggregated proteins is possibly a consequence of stimulation of apoptotic responses (153) . Apoptosis proceeds through ROS production and increases in Ca2+ levels that are followed by the activation of caspases (154) . In addition, the mitogen-activated protein kinase (MAPK) pathway activation has been observed in protein misfolding diseases (155) . The MAPK pathway contributes to a number of reactions when the cell responds to various stressful conditions such as oxidative stress, cytokines, and heat shock (156 157 158) .

In addition to their direct toxic effects, misfolded proteins can also promote inflammatory responses (96) . In the brain of patients with Alzheimer’s disease, neuroinflammation is characterized by local stimulation of the complement system, acute-phase responses, increased expression of C-reactive protein, and activation of inducible nitric oxide synthase and prostanoid-generating cyclooxygenase-2 (159 , 160) . It has been found that amyloid-β activates microglia cells (161) , which then release a variety of proinflammatory mediators including cytokines, ROS, complement factors, secretory products, free radical species, and nitric oxide, which all contribute to chronic inflammation and neuronal cell death (162) . Chronic inflammation is not restricted to Alzheimer’s disease; similar processes have been observed in most protein misfolding diseases (11 , 163 164 165) . For example, the role of microglial cells in neuroinflammation is similar to the key role played by macrophages in the pathology of atherosclerosis and diabetes mellitus (166) . They share the same progenitors and are able to phagocytose debris and produce cytokines, ROS, and other secretory products (167) . Macrophages express pattern recognition receptors, including scavenger receptors and Toll-like receptors (168) . These receptors, which participate in the removal of foreign substances and debris (see Misfolded Protein Binding Molecules), comprise an important part of the innate immune system (169) .

Misfolded protein binding molecules
Various molecules associate or colocalize with misfolded proteins at the sites of the deposits (Table 3 ). Most of them are cell surface receptors; others are soluble proteins. The most common misfolded protein binding receptors are the scavenger receptors. In contradiction with the classic one receptor-one ligand theory, pattern recognition receptors, such as the scavenger receptors, are exceptional because they recognize multiple ligands. The exact nature of the ligand-receptor interaction is not known. Hence, one important task is to determine a common ligand structure to understand how such diverse proteins can interact with the same receptor.


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  		Table 3. Binding molecules for misfolded proteins

CD36 is a class B scavenger receptor that was first described as a platelet glycoprotein (170) . CD36 was thought to be a receptor for thrombospondin, and then it was recognized as a multiligand scavenger receptor with remarkably diverse ligands such as apoptotic cells, modified LDL, amyloid-β, erythrocytes infected with malaria, and anionic phospholipids (for references, see Table 3 ). Accordingly, CD36 is involved in many biological processes, i.e., cardiovascular diseases, malaria infection, renal failure, and cancer.

The receptor for advanced glycation end products (RAGE) is associated with diverse pathological conditions including late diabetic complications, neuropathy, and chronic inflammation (171) . In addition to advanced glycation end products, many more ligands have been described for RAGE. Most of them are proinflammatory molecules or particles derived from necrotic cells (see references in Table 3 ).

The LDL receptor-related protein (LRP) is a large cell surface receptor that recognizes various ligands such as lipoproteins, proteinases, extracellular matrix proteins, bacterial toxins, viruses, and intracellular proteins (172) .

There are various hypotheses about the cellular mechanisms that cause misfolded protein-triggered inflammation and cytotoxicity. RAGE and LRP are known to have a crucial role in regulation of the amyloid-β levels under physiological conditions in the brain (173) , because the transport of amyloid-β through the blood-brain barrier is mediated almost exclusively by the strictly balanced work of the two receptors. Whereas LRP clears amyloid from the brain parenchyma into the cerebral capillaries, RAGE mediates the transcytosis of the protein (173) .

The serine protease tissue-type plasminogen activator (tPA) is a key component of blood clot lysis, i.e., fibrinolysis. After the binding of tPA to fibrin, plasminogen is converted by activated tPA to active plasmin, which then chops the fibrin network into small pieces. As a novel and more general function for tPA beyond fibrinolysis, our group noted that the appearance of the common cross-β structure in proteins without sequence similarities enables tPA to bind and mediate plasmin formation (174) . The role of tPA in Alzheimer’s disease is under investigation. In mouse models, injected amyloid-β is cleared by tPA (175) . However, other reports showed that amyloid-β can lead to excessive tPA activation and toxicity (176) . This finding is in line with other observations showing that elevated tPA is neurotoxic (177) .

Serum amyloid P is an acute-phase serum protein, and its physiological role is not completely understood. It binds negatively charged carbohydrates and colocalizes with the protein deposits in the brain of patients with Alzheimer’s disease (178) or hemodialysis-related amyloidosis (179) . When radiolabeled, it can be used to visualize amyloid in vivo in humans (180) .

Complement component C1q binds to amyloid-β and is colocalized with thioflavine-positive plaques in the brain of patients with Alzheimer’s disease (181) . It forms complexes with β2-microglobulin in the sera of patients with hemodialysis-related amyloidosis (182) . Interestingly, the binding site is localized to the C1q collagen-like residues, a novel interaction site for antibody-independent activation of C1 (183) . Furthermore, C1q binds to the modified form of the prion peptide (184) .

Clusterin (ApoJ) is a constitutively secreted extracellular chaperone that binds to exposed hydrophobic regions on non-native proteins (185) . Clusterin binding is restricted to oligomeric protein species of lysozyme and amyloid-β that are present at low concentrations during the nucleation phase of the aggregation reaction (186 , 187) .

Naturally occurring amyloid proteins
A number of amyloids have no known pathological effects in disease, and recently it has been proposed that amyloid formation is not exclusively associated with pathological conditions but also occurs under physiological conditions. Below and in Table 4 we provide a brief summary of the data identifying naturally occurring amyloid proteins and their functions. For more information we refer the reader to a specialized review on this topic and references therein (246) as well as to two other reviews that discuss functional amyloid and amyloid formation with no known pathological effects (247 , 248) .


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  		Table 4. Naturally occurring amyloid proteins

For example, nonpathogenic amyloid has been detected in mammals in melanosome biogenesis and melanin formation in vitro (249) . Melanin is a pigment particle that protects the skin against pathogens, toxic small molecules, and UV radiation. It is present in most eukaryotic phyla ranging from fungi to insects and humans. There are two other mammalian proteins with suggested functional amyloid formation. The isolated type III domain of murine fibronectin is unstable and assembles into amyloid-like fibrils (250) . The type III domain is an alternative splicing site, which is only expressed during embryogenesis, wound healing, and tumorigenesis and it is responsible for cell membrane binding. Amphoteric has been noted to form amyloid and to have the capacity to bind Alzheimer’s peptide amyloid-β in vitro (251) and is involved in the neuronal development of human brain. High levels of amphoteric are released in the blood in septic shock, and it also acts as a proinflammatory and procoagulant mediator.

Besides mammalian proteins, amyloid fibril formation was identified on proteins on the surfaces of fungi and bacteria such as the curly and tai fibrils of Escherichia coli and Salmonella or hydrophobics on fungi (252) . These bacterial and fungal amyloid derivatives play a crucial role in the invasion of the host. Amyloid formation that occurs inside yeast proteins, including Sup35p and Ure2p, is referred to as yeast prions with roles in transcription and translation, respectively (253) .

The identification of amyloid proteins that are not associated with diseases and have physiological functions, brings into question the correct use of the term "misfolded protein" and raises further questions regarding what "proper folding" is. These proteins appear to have an alternative folding that is amyloid. The indications that amyloids can have physiological importance are fascinating initiatives, but whether all these amyloids are true functional proteins in vivo remains to be established.


   THERAPEUTIC APPROACHES TO PROTEIN MISFOLDING DISEASES
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 ABSTRACT
 THE APPEARANCE OF PROTEINS
 PROTEIN MISFOLDING DISEASES
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There is no efficient therapy for inhibiting or reversing protein aggregation and deposition in patients with protein misfolding diseases. In the past decade, our understanding of the underlying mechanisms during development of protein misfolding diseases has much improved, opening new perspectives for designing more efficient medications against these highly devastating disorders. In this section we briefly highlight recent findings that provide new concepts for inhibition of protein aggregation and its proinflammatory and cytotoxic effects. The main approaches fall into the following categories: 1) small compounds that inhibit aggregation; 2) immunotherapy (antibody therapy and vaccination); and 3) compounds that interfere with amyloid-cell or amyloid-protein interactions or responses thereof. Alternative therapeutic agents that are not directly targeting amyloid, such as donepezil (cholinesterase inhibitor) or memantine (N-methyl-D-aspartate receptor antagonist), are used but have shown only modest benefit.

Extensive studies on protein misfolding described the inhibition of protein aggregation by small compounds, such as 2,4-dinitrophenol (258) , di- and trisubstituted aromatic molecules (259) , curcumin, β-cyclodextrin derivatives, hematin, meclocycline, indomethacin, and Congo red (260) . The inhibitory effect involves stabilization of the native fold of potentially amyloidogenic proteins or inhibition of their oligomerization or fibrillarization (54 , 260 261 262) . For example, the fibrillarization of transthyretin peptide that results in its accumulation in organs in human amyloidosis (Table 2) is blocked when transthyretin is complexed with retinol-binding protein and thyroxine (263) .

One of the most challenging possibilities among the potential therapeutic approaches for protein misfolding diseases is antibody therapy. In animals, monoclonal antibodies have been raised by passive immunization against critical regions of the amyloid-β that participate in the aggregation process. These antibodies then improved cognitive function and amyloid pathological effects after a series of injections into transgenic mice that express human APP and serve as a model for Alzheimer’s disease (264 , 265) . Clinical trials with passive administration have been initiated (see Table 5 ). Nevertheless, the possibilities of active immunization, when the harmful protein is injected and it stimulates antibody production that can eliminate the aggregated self-proteins or interfere with further aggregation, are limited because of the tolerance against self-proteins. Through mechanisms that are incompletely understood, vaccines can overcome tolerance. Immunized transgenic animals showed reduced protein deposition in the brain (266) and mucosal immunizations against prion proteins showed a delay of disease (267) . Active and passive immunization experiments in animal models for Alzheimer’s and prion diseases offered great perspectives for the immunotherapy against amyloidogenic proteins in the treatment of protein misfolding diseases (268 , 269) . However, after the early success of animal models, the first human trials had to be terminated because of unexpected severe meningoencephalitis in patients (270) . Recent studies focus on passive immunizations, i.e., the generation of conformation-specific antibodies that recognize structural epitopes of misfolded proteins and discriminate between fibrillar (271) and oligomeric (137) conformation. By using new strategies, novel vaccines against Alzheimer’s disease, stimulating immune responses against amyloid-β hopefully without provoking brain inflammation risk, are under development or entering clinical trials (272) .


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  		Table 5. Examples of approaches and drugs targeting protein aggregation or uptake

The receptor for RAGE mediates the uptake of misfolded β2-microglobulin in patients with dialysis-related amyloidosis (273) and contributes to the influx of amyloid-β from the blood into the brain (173) . Therefore, RAGE has been in the focus for novel drugs targeting its interaction with amyloid-β (Table 5) . Elevated levels of the soluble RAGE that lacks the transmembrane domain and therefore circulates in plasma, is associated with reduced risk of coronary artery disease, hypertension, the metabolic syndrome, arthritis, and Alzheimer’s disease (274) . Furthermore, the binding of ligands to RAGE contributes to both development and progression of vascular diseases including atherosclerosis (275) . Animal studies show that blockage of the interaction prevents the development of these diseases (276) , which stimulated companies to develop drugs to target the interaction of RAGE and amyloid-β (Table 5) . The soluble form of RAGE is another promising therapeutic target for inflammation-related disorders including protein misfolding diseases (215 , 276) (Table 5) .

In the central nervous system, tPA is implicated in pathological and physiological processes (175) . Cerebral tPA activity is decreased during aging in normal mice and is further lowered in mice that express high levels of amyloid-β (277) . This result supports its role in the clearance of amyloid-β (278) . Conversely, tPA is overexpressed in amyloid-rich areas in the brain of patients with Alzheimer’s disease (279) and mediates neuronal apoptosis that is precluded by plasmin (280) . However, inflammation increases the amount of tPA inhibitors, which prevents the destruction of amyloid-β proteins by obstructing the action of tPA (281) . Taken together, these results show that tPA plays a critical role in the clearance of amyloid proteins through tPA activation and subsequent plasmin generation. However, in the absence of plasmin, tPA induces toxic effects. Therefore, tPA is an interesting target for protein misfolding diseases.


   ACKNOWLEDGMENTS
 
E.H. received financial support from the International Visegrad Fund and Huygens Scholarship Programme, The Netherlands. M.F.B.G.G. kindly acknowledges financial support from the International Society for Alzheimer Research, The Dutch Thrombosis Foundation, The Association for International Cancer Research, The Netherlands Association for Scientific Research, The Technology Association (STW Valorisation), and the Ministry of Economical Affairs (Biopartner). M.F.B.G.G. is a shareholder and part-time employee of Crossbeta Biosciences BV.

Received for publication October 2, 2007. Accepted for publication January 31, 2008.


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 MOLECULAR BASIS OF PROTEIN...
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