Sci. Aging Knowl. Environ., 21 September 2005
Vol. 2005, Issue 38, p. pe28
[DOI: 10.1126/sageke.2005.38.pe28]


Membrane Permeabilization: A Common Mechanism in Protein-Misfolding Diseases

Hilal A. Lashuel

The author is at the Integrative Biosciences Institute, Laboratory of Molecular Neurobiology and Neuroproteomics, École Polytechnique Fédérale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland. E-mail: hilal.lashuel{at}

Key Words: protein misfolding • neurodegenerative disease • amyloid pore hypothesis • protofibril • Alzheimer's disease • Parkinson's disease


The extracellular and/or intracellular deposition of misfolded proteins in the form of fibrillar aggregates, referred to as amyloid fibrils, is a defining neuropathological hallmark shared by several clinically and pathologically distinct neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), and prion diseases (see Andersen Review, Berezovska Perspective, Trojanowski Perspective, and "Detangling Alzheimer's Disease"). The finding of these fibrillar deposits in the vicinity of dying neurons and tissues led many to embrace the hypothesis that amyloid fibrils cause neurodegeneration and/or organ dysfunction in amyloid diseases (the amyloid fibril hypothesis). Despite an extensive body of genetic, pathologic, and biochemical data linking the process of amyloid formation to these diseases, the mechanisms by which this process causes neurodegeneration and cytotoxicity, as well as the identity of the pathogenic species, remain unknown. The lack of means to monitor and study protein misfolding and aggregation in vivo combined with our inability to observe the pathogenic events associated with these processes in vivo have contributed substantially to this gap in knowledge and to the absence of effective diagnostic tools and therapeutic strategies to treat the underling causes of these diseases.

Over the past two decades, animal modeling, cell biological, biophysical, and biochemical approaches have been brought to bear on different aspects of protein fibrillogenesis and its relation to neurodegeneration and disease pathology. Several mechanistic themes and working hypotheses have emerged from the synergistic applications of these multidisciplinary approaches.

The Toxic Protofibril Hypothesis

Amyloid formation is a complex process and proceeds through a series of discrete {beta}-sheet-rich oligomeric intermediates that appear before fibrils form and disappear upon fibril formation in vitro (1-3) (see Obrenovich Perspective). These intermediates exist as a heterogeneous mixture of aggregates of various sizes and morphologies (globular, chainlike, and annular structures) and are collectively called protofibrils (4). The transient formation of protofibrils has been observed during the in vitro fibrillization of all amyloid-forming proteins studied thus far, irrespective of whether these proteins are linked to human disease. Oligomeric and protofibrillar intermediates of similar morphologies have also been observed in human cerebrospinal fluid and human cerebral cortex (5), as well as in neuritic amyloid plaques and inclusions from AD (6) and brains from individuals with the neurodegenerative disease multiple system atrophy (MSA) (7), respectively. Together, these observations support the notion that protofibrils are obligate intermediates that are likely to exist in vivo, albeit transiently. This possibility, combined with the failure of the amyloid fibril hypothesis to explain several pathological and clinical observations that characterize many amyloid diseases, gave rise to the toxic protofibril hypothesis, which implicates protofibrils, rather than the fibril, as the toxic species. Consistent with this hypothesis, nonfibrillar oligomeric forms of {beta} amyloid peptide (A{beta}) were demonstrated to alter neuronal function and/or cause cell death (8-11). Since their discovery in 1996-1997, mounting evidence from pathological findings, animal modeling, and in vitro (cell culture and test tube experiments) studies continue to converge in support of this hypothesis (4, 12).

Mechanisms of protofibril-induced toxicity

Despite intensive studies on amyloid formation, our current understanding of the molecular mechanism of protofibril formation, the three-dimensional structure of protofibrils, and the mechanism(s) by which they exert their toxicity remains limited. Mitochondrial dysfunction (13, 14) (see Ogawa Perspective and Giasson Perspective), Golgi fragmentation (15), transcriptional dysregulation, altered chaperone activity, impairment of the protein degradation machinery (16, 17) (see Gray Review), oxidative stress, and membrane disruption have all been proposed to play key roles in the initiation and progression of neurodegeneration and cytotoxicity in protein-aggregation diseases (18). It is likely that cell death in neurodegenerative diseases occurs by more than a single mechanism. Indeed, emerging data from animal and cell culture models support a strong interplay between these different pathogenic processes. Despite this uncertainty, this Perspective will focus on a working hypothesis in which a single protein aggregate (the amyloid channel or amyloid pore) is responsible for initiating a pathogenic cascade of events that culminates in neuronal death by unregulated membrane permeabilization (Fig. 1).

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Fig. 1. Pore formation by amyloid-forming proteins may occur by one of several mechanisms similar to those used by evolved pore-forming protein toxin (PFT). The mechanism of pore formation by PFT includes a series of complex events involving binding to the membrane, oligomerization, and insertion into the membrane. The top portion of the figure is a schematic representation showing the various intermediates that form during amyloid fibril formation in vitro. For simplicity, only the most commonly observed oligomers and protofibrillar (globular, chainlike, and pore-like) structures are shown. The bottom portion of the figure shows that, like pore-forming amyloid proteins, PFTs are usually released as water-soluble species, and pore formation requires that these proteins undergo conformational changes and self-assembly either prior to or upon their interactions with the membranes. Studies on pore formation by A{beta}, {alpha}-synuclein, and other amyloidogenic proteins demonstrate that pore formation can occur upon reconstitution of soluble monomers into lipid bilayers or upon addition of preformed oligomers (spherical and pore-like protofibrils) (30, 35, 38, 43), but not the monomers to synthetic membranes. The formation of A{beta} and {alpha}-synuclein prepore oligomers could contribute to lowering the energy barrier associated with the simultaneous insertion of a large {beta}-sheet pore into the membrane.

Pore formation and membrane permeabilization: Common pathogenic mechanisms in protein-misfolding diseases

Disruption of Ca2+ homeostasis and generation of reactive oxygen species have long been recognized as key events in the pathogenesis of several neurodegenerative diseases, including AD (19). Cellular factors responsible for initiating these events and the mechanism by which they contribute to the neurodegeneration and cytotoxicity remain poorly understood. In 1993, Arispe and colleagues demonstrated that A{beta}, the primary component of amyloid plaques, forms calcium channels in lipid bilayers and proposed that channel formation by A{beta} is partially or wholly responsible for A{beta}-induced toxicity in AD (20, 21). This finding has been reproduced many times, in several different laboratories, using many membrane models (21-34). Later, Lal and colleagues showed that reconstitution of A{beta} into artificial lipid bilayers produces uniform pore-like structures with an outer diameter of 8 to 12 nm and an inner diameter of 2 nm (Fig. 2 A ) (30, 35). Further studies from the laboratories of Nelson Arispe, Bruce Kagen, and Joseph Kourie suggest that channel formation is a property that is shared by most, if not all, amyloid-forming proteins studied thus far. This hypothesis is strengthened by the findings of Lal and colleagues that several amyloid-forming proteins, including A{beta} (1-40), {alpha}-synuclein (mutations in which are associated with PD), the British dementia peptide (ABri) [mutations in which are associated with familial British dementia (FBD)], the apolipoprotein serum amyloid A (SAA), and the hormone amylin (pancreatic deposits of which are associated with type 2 diabetes) form pore-like structures and exhibit channel-like activity when reconstituted in lipid bilayers (35). The high-resolution atomic force microscopy (AFM) images reveal tantalizing images of pore-like structures of variable diameter and channel-like activity. These images reveal a common structural feature, in addition to the fibril structure, that is shared by amyloid-forming proteins and point toward a common mechanism of toxicity in protein-misfolding diseases. Consistent with this hypothesis, antibodies raised against protofibrillar A{beta} were reported to recognize protofibrillar intermediates derived from other amyloidogenic proteins [for example, {alpha}-synuclein, polyglutamine, the plasma protein transthyretin, amylin, lysozyme, human insulin, and prion peptide (PrP) 106-126] and inhibit protofibril-induced toxicity by these proteins (36).

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Fig. 2. The propensity of amyloid proteins to form pore-like structures in solutions correlates very well with their channel and membrane permeabilization properties. Annular pore-like structures with variable diameters have been shown to form during the in vitro fibrillogenesis of disease-associated mutant forms of A{beta} (1-40) {Arctic variant [Glu22->Gly22 (E22G)]} (48, 49), {alpha}-synuclein [Ala53->Thr53 (A53T) and Ala30->Pro30 (A30P)] (49, 42), SAA (65), amylin (Lashuel and Lansbury, unpublished results) and ABri (45) in solution. (A) Electron microscopy images (1-9) of pore-like structures formed by {alpha}-synuclein (A53T); similar images for the other proteins can be viewed at ( (B) Formation of pore-like structure upon reconstitution into lipid bilayers by A{beta}, {alpha}-synuclein, the amyloidogenic peptides ABri and ADan (which have been implicated in familial British and Danish dementia), amylin and SAA. [(B) is reproduced from (35), copyright (2005) National Academy of Sciences, U.S.A., with permission.]

Formation of pore-like structures in solution correlates very well with the permeabilization activity of the pore-forming protein

Interestingly, several amyloid proteins, including A{beta} (1-40), {alpha}-synuclein, ABri, SAA, amylin, superoxide dismutase-type 1 (SOD1), polyglutamine peptides [Lys-Lys-(Gln)40-Lys-Lys], lysozyme, human insulin, and PrP 106-126, form pore-like structures in solution in the absence of membrane. In some cases, the propensity of the protein to form pore-like structures correlates very well with its ability to permeabilize membranes. For example, {alpha}-synuclein protofibrils (but not the monomers or the fibril) were shown to bind to synthetic membranes and permeabilize vesicles in a size-selective manner, consistent with permeabilization by a pore-like mechanism (37, 38). Detailed characterization of the {alpha}-synuclein protofibrils revealed pore-like structures, with pore sizes that correlate very well with the observed size selectivity. These structures resemble, in morphology and dimension, membrane-spanning pores that are formed by protein toxins (for example, hemolysin, latrotoxin, and aerolysin) (39-41). Only {alpha}- and {gamma}-synuclein were shown to bind and permeabilize synthetic membranes, consistent with the propensity of these proteins to form annular protofibrils in solution. Neither pore formation nor membrane permeabilization activity was observed in the case of the non-amyloidogenic member of the synuclein family proteins, {beta}-synuclein, thus strengthening the link between the formation of pore-like structures and membrane disruption by {alpha}-synuclein protofibrils.

Pathogenic mutations promote pore formation, membrane permeabilization, and toxicity

Pathogenic mutations in A{beta}, {alpha}-synuclein (42-44), ABri (45), and SOD1 (46, 47), associated with the familial forms of AD, PD, FBD, and ALS, respectively, form pore-like structures more rapidly than the wild-type (WT) proteins. The size and morphology of these aggregates resemble greatly the pore-like aggregates formed in lipid bilayers. Furthermore, the form of A{beta} that is closely linked to AD pathogenesis [A{beta} (1-42)] exhibits higher propensity to form channels than does A{beta} (1-40), consistent with its increased propensity to aggregate and form annular protofibrils in vitro (Lashuel and Lansbury, unpublished). Therefore, the fact that the WT protein is also capable of forming pore-like structures (42, 47-49), albeit more reluctantly, suggests that common pathogenic mechanisms associated with a gain of a toxic function underlie the familial and sporadic forms of these diseases. In the absence of pathogenic mutations, several factors that favor protein aggregation could also promote membrane interactions and the formation of amyloid pores. These factors include, but are not limited to (i) changes in the pathogenic microenvironment (such as altered pH, changed membrane composition, or increased oxidation); (ii) increased expression of the amyloid-forming proteins (50, 51); (iii) impaired degradation of the amyloidogenic protein by the proteasome (52); (iv) interaction of the amyloid-forming proteins with specific membrane environments and/or other binding partners; and (v) posttranslational modifications of the amyloidogenic proteins. Neurodegeneration and cell death might be triggered by an increase in the concentration of protofibrils or a selective population of protofibrils with a particular morphology, such as the amyloid pores or other precursors with pore-forming potential [e.g., globular oligomers (Fig. 1)] upon interaction with membranes.

Are pore formation and channel-like/pore-like activity by amyloid proteins two faces of the same coin?

Several lines of evidence support a strong link between the propensity of amyloid proteins to form pore-like structures and their channel activity, membrane permeabilization activity, and neurotoxicity in neurodegenerative diseases [for recent reviews, see (16, 27, 4)]. (i) The propensity of nonfibrillar oligomers of amyloid-forming proteins [including A{beta} (32, 49), amylin (54, 55), polyglutamine repeats (55), SAA (56), prion proteins (57, 58), and {alpha}-synuclein (37, 38, 42)] to form ion-permeable pores correlates with their ability to self-assemble into pore-like structures in vitro. (ii) Conformational changes ({beta}-sheet formation) and oligomerization are two key requirements for the formation of protofibrils and channels. (iii) Molecules known to inhibit A{beta} oligomerization were reported to inhibit channel formation but had no effect on preformed channels (32, 59, 60). (iv) Electrophysiological measurements indicate that A{beta}, amylin, and PrP 106-126 form nonselective and/or unregulated channels in lipid bilayers, consistent with the large pore sizes observed by electron microscopy and AFM in vitro, which allow the passage of ions (Ca2+) as well as small molecules (for example, dopamine). (v) Channels formed by amyloidogenic proteins are heterogeneous, consistent with the propensity of these proteins to form heterogeneous amyloid pores in vitro (42, 48), suggesting that oligomers in multiple states are capable of channel formation. (vi) Interactions between protofibrillar species of A{beta} and {alpha}-synuclein and artificial membranes were observed to be irreversible, suggesting permeabilization by an insertion mechanism. Likewise, amylin and PrP 106-126 form irreversible channels (25, 27, 54). Furthermore, pore-like protofibrillar intermediates have also been observed during the fibrillogenesis of all amyloid-forming proteins shown to have channel-like or pore-like properties in vitro, supporting the notion that formation of the pore and formation of the fibril are tightly linked.

What is the evidence for pore formation and inappropriate membrane permeabilization in neurodegenerative disease?

Our current understanding of the mechanism of amyloid formation in vitro and in vivo suggests that oligomers and protofibrils, including the amyloid pores, should exist at one time, albeit only in small amounts in the brains of patients with neurodegenerative disease. Although there is no direct evidence linking channel/pore formation by amyloid proteins to the pathology of their respective diseases, a number of studies on materials extracted from diseased brains showed protein aggregates with properties that are consistent with their being protofibrillar, including globular oligomers and pore-like structures (61). Direct evidence for the existence of amyloid pore-like structures in vivo has been provided by the detection of annular {alpha}-synuclein structures, similar to those seen in in vitro preparations, in inclusions purified from post-mortem brain tissues of an MSA patient (7, 62). These observations provide direct evidence that pore-like structures do exist in vivo and provide another compelling piece of circumstantial evidence for the toxic protofibril hypothesis. However, it is important to emphasize that finding pore-like structure in diseased tissue has no real bearing on the question as to whether they are pathogenic; moreover, failure to find them will not disprove the pore hypothesis.

If the amyloid pore is the neurotoxic species, signs of inappropriate membrane permeabilization should exist in the diseased brain or tissues. Unfortunately, this may be impossible to dissect, because permeabilization would be expected to trigger a complex cascade of events that would obscure evidence of the upstream initiating event. Formation of unregulated pores at the mitochondrial membrane could result in altered Ca2+ homeostasis (13, 14) and the release of cytochrome C and other proapoptotic molecules, ultimately causing increased oxidative stress and apoptosis (14). These are features of all neurodegenerative diseases, but are most clearly seen in postmortem ALS brain, in which mitochondrial swelling and cytochrome C release are invariant features (63, 64). One might also expect to see Golgi fragmentation, and one does (15), or permeabilization of the endoplasmic reticulum membrane, which could lead, among other things, to retrograde transport of aggregation-prone proteins to the cytosol.

Testing the Amyloid Pore Hypothesis

Although a strong circumstantial case can be made in support of a link between formation of pore-like structures and channel/pore activity by amyloid proteins, the relevance of pore formation to disease, as proposed by the channel/pore hypothesis, is not at all clear. Therefore, it must be emphasized that there remains much work to establish the validity of the channel/pore hypothesis. The ultimate proof that amyloid pores are partially or wholly responsible for initiating the pathogenic cascade associated with neurodegeneration and cytotoxicity in amyloid diseases rests on our ability to demonstrate that the disease phenotype in transgenic animals could be predicated based on the in vitro behavior of mutant forms of amyloid-forming proteins with altered pore-forming properties. Small molecules or mutations that inhibit pore formation should abolish the membrane permeabilization activity of the protein in vitro and inhibit the progression of the disease in transgenic animal models of the disease. Conversely, small molecules or mutations that favor and promote pore formation would be expected to enhance toxicity and accelerate the rate of disease progression. In any event, further investigation of the biophysical and biological properties of amyloid pores and the factors that govern their formations (in vitro and in vivo) should aid in the investigation of their physiologic and pathologic properties and would facilitate further experiments aimed at testing the amyloid pore hypothesis.

Implications for Therapeutic Strategies

The amyloid diseases discussed here affect well over 15 million individuals worldwide, and the affected population is growing. No available treatments address the underlying process of neurodegeneration and cell death. Thus, the debate over what is causing neuronal death is more than an academic exercise, as blocking the cell-death pathway or, more likely, pathways, at their source would be the optimal therapeutic strategy. Targeting the formation of small ordered aggregates, like protofibrils and amyloid pores, may be an effective strategy. That being said, it is likely that the mechanism for toxicity reviewed here is not the only toxic pathway.

September 21, 2005
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Citation: H. A. Lashuel, Membrane Permeabilization: A Common Mechanism in Protein-Misfolding Diseases. Sci. Aging Knowl. Environ. 2005 (38), pe28 (2005).

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