Invited review
A unifying framework for amyloid-mediated membrane damage: The lipid-chaperone hypothesis

https://doi.org/10.1016/j.bbapap.2022.140767Get rights and content

Highlights

  • •

    The lipid-chaperone hypothesis is a general mechanism of amyloid membrane damage.

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    Amyloidogenic proteins share a common molecular mechanism in membrane damage.

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    To understand fast interaction protein-membrane experimental and simulations are needed.

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    In effective drugs development, the role of free lipid should be considered.

Abstract

Over the past thirty years, researchers have highlighted the role played by a class of proteins or polypeptides that forms pathogenic amyloid aggregates in vivo, including i) the amyloid Aβ peptide, which is known to form senile plaques in Alzheimer's disease; ii) α-synuclein, responsible for Lewy body formation in Parkinson's disease and iii) IAPP, which is the protein component of type 2 diabetes-associated islet amyloids. These proteins, known as intrinsically disordered proteins (IDPs), are present as highly dynamic conformational ensembles.

IDPs can partially (mis) fold into (dys) functional conformations and accumulate as amyloid aggregates upon interaction with other cytosolic partners such as proteins or lipid membranes. In addition, an increasing number of reports link the toxicity of amyloid proteins to their harmful effects on membrane integrity. Still, the molecular mechanism underlying the amyloidogenic proteins transfer from the aqueous environment to the hydrocarbon core of the membrane is poorly understood.

This review starts with a historical overview of the toxicity models of amyloidogenic proteins to contextualize the more recent lipid-chaperone hypothesis. Then, we report the early molecular-level events in the aggregation and ion-channel pore formation of Aβ, IAPP, and α-synuclein interacting with model membranes, emphasizing the complexity of these processes due to their different spatial-temporal resolutions. Next, we underline the need for a combined experimental and computational approach, focusing on the strengths and weaknesses of the most commonly used techniques. Finally, the last two chapters highlight the crucial role of lipid-protein complexes as molecular switches among ion-channel-like formation, detergent-like, and fibril formation mechanisms and their implication in fighting amyloidogenic diseases.

Introduction

Intrinsically disordered proteins (IDPs) [1] in the aqueous phase are characterized by a not well-defined secondary and tertiary structure since their backbone explores a large number of conformations [2]. Some of these proteins are called metamorphic or chameleonic [3,4], due to the possibility that identical amino acid sequences can adopt either α-helix, β-sheet, or random coil secondary structures. IDPs perform important biological functions, such as cellular signaling and regulation [5]. Amylin (IAPP), amyloid-beta (Aβ), and α-synuclein (αS) proteins linked with type 2 diabetes (T2D), Alzheimer's (AD), and Parkinson's (PD) diseases, respectively, show both IDPs and chameleonic nature. Human IAPP is a 37-amino acids hormone containing a disulphide bridge [6] co-secreted with insulin (ratio 1:100) from islet β-cells. In physiological conditions, insulin, together with glucagon, regulates the level of glucose in the blood. In diabetes type 2, amyloid deposition of IAPP has been associated with islet β-cells death [7]. Aβ is a 39–43 amino acids peptide derived from the cleavage by β and γ secretase of the amyloid precursor protein (APP) [[8], [9], [10], [11]]. Aβ performs several physiological functions, including the regulation of synaptic plasticity, the facilitation of neuronal growth and survival [4,12,13]. The αS protein senses membrane curvature and contributes to synaptic trafficking, vesicle budding, and regulation of dopamine release [14,15]. In pathologic conditions, the accumulation of Aβ and αS is toxic to neurons and the mechanism behind has been associated with membrane disruption and ion dysregulation [16].

Hence, the study of IDPs-membrane interaction appears to be crucial to understand the molecular toxicity mechanism. However, due to the great complexity belonging to cell membranes, a bottom-up approach is strongly needed. Therefore, model membranes are useful to unravel the basic interaction between their constituents and other chemical entities in the aqueous phase. For this purpose, large unilamellar vesicles (LUVs) are the most popular and well-characterized model membranes built at the different complexity levels of composition, to mimic various cell membranes and organelle as well as drug delivery systems [7,[17], [18], [19]].

Although there is a large consensus that toxicity originates from membrane damage, a general molecular mechanism remains unsettled. In this framework, some hypotheses have been proposed: i) the amyloid hypothesis considering fibril structures responsible for membrane damage [20,21]; ii) the toxic oligomer hypothesis in which the toxic species are small prefibrillar amyloidogenic proteins [22], able to damage the membrane in two independent [23] steps: transmembrane ion-channel-like-pores and detergent-like mechanism [20,21,24,25] iii) the lipid-chaperone hypothesis in which free lipids in the aqueous phase form a stable lipid-amyloidogenic protein complex highly prone to insert into the bilayer [[24], [25], [26], [27], [28], [29], [30]]. The latter hypothesis assumes specific relevance considering that an abnormal accumulation of amyloidogenic peptides, together with a dysregulated phospholipase activity, high levels of unsaturated or short acyl-chains phospholipids, are found in individuals who develop T2D, AD, and PD [[31], [32], [33], [34], [35]]. Moreover, it is crucial to highlight that the hypothesis mentioned above shall not be considered exclusive but rather a solid bridge between the other two. The present review discusses the toxicity models of amyloidogenic proteins focusing on our recently developed lipid-chaperone hypothesis. We identified a common mechanism shared by all the amyloidogenic and non-amyloidogenic proteins, i.e., human and rat-IAPP (h-IAPP and r-IAPP), Aβ(1–40) and α and β-synuclein (αS and βS). In addition, the review describes the fundamental steps that led us to formulate this theory and the need for a multidisciplinary approach to the study of amyloidogenic IDPs and their relation with T2D, AD, and PD diseases.

Section snippets

Toxicity models of amyloidogenic proteins

In 1984, George Glenner purified the Aβ peptide from cerebrovascular amyloid fibrils associated with AD [36]. In the early 1990s, three different mutations were discovered in the genes encoding for the APP [37], and for the secretases (prenisilin 1 and 2) [38,39], associated with the onset of the familiar form of AD. Both the observations of Aβ being the main component of plaques and the identification of such mutations favoring the aggregation of Aβ in familiar AD led to the formulation of the

Synergism between simulations and experiments

Local changes of protein loops and side chains take place in less than a second (10−14 - 10−1 s). Rigid body movements, such as subunit and domain adjustments, occur instead in the range of microseconds and seconds, whereas protein folding and oligomerization take place in 10−14 - 10−1 s. To capture all of these movements ultrafast techniques able to explore a portion of space in the range of 0.01–10 Å are needed, but also techniques capable of looking at large-scale behavior in the range of

The theoretical model

The framework behind the lipid-chaperone hypothesis relies on the thermodynamic partitioning of lipids between the aqueous phase and membrane-like organelles (bilayers, micelles, etc.). Thermodynamics states that there will always be a concentration of free lipids at equilibrium in the aqueous phase, in dynamical exchange with the lipid phase. This concentration is defined as the Critical Micellar Concentration (CMC). Our initial hypothesis was that these free lipids in solutions could interact

Conclusions and new directions

The lipid-chaperone hypothesis is based on the presence of free lipids in the aqueous phase, forming a stable complex with the amyloidogenic protein, which is then transported into the bilayer. This idea is supported by in vitro experiments on amyloidogenic proteins such as h-IAPP, Aβ, and αS, and non-amyloidogenic r-IAPP and βS, taken as control [30]. From these data, two relevant questions arise: What are the sources of free lipids? Does the lipid-chaperone hypothesis assume a biological

Declaration of Competing Interest

All authors declare that there is no financial or personal relationships that may be perceived as influencing their work.

Acknowledgement

All the authors are grateful to Professor Antonio Raudino, who passed away in 2021, for envisioning and contributing to the development of the Lipid-chaperone hypothesis.

C.T. would like to acknowledge the International Max Planck Research School for Many-Particle Systems in Structured Environments hosted by the Max Planck Institute for the Physics of Complex Systems, Dresden, Germany. The work has been performed under the Project HPC-EUROPA3 (INFRAIA-2016-1-730897), with the support of the EC

References (200)

  • G.G. Glenner et al.

    Alzheimer’s disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein

    Biochem. Biophys. Res. Commun.

    (1984)
  • L. Pieri et al.

    Fibrillar α-Synuclein and huntingtin exon 1 assemblies are toxic to the cells

    Biophys. J.

    (2012)
  • T. Okada et al.

    Formation of toxic fibrils of Alzheimer’s amyloid β-protein-(1–40) by Monosialoganglioside GM1, a neuronal membrane component

    J. Mol. Biol.

    (2007)
  • C.R. Jack

    Age-specific population frequencies of cerebral β-amyloidosis and neurodegeneration among people with normal cognitive function aged 50–89 years: a cross-sectional study

    Lancet Neurol.

    (2014)
  • J. Zhao

    Probing ion channel activity of human islet amyloid polypeptide (amylin)

    Biochim. Biophys. Acta BBA

    (2012)
  • H. Olzscha

    Amyloid-like aggregates sequester numerous metastable proteins with essential cellular functions

    Cell

    (2011)
  • H. Juhola

    Negatively charged gangliosides promote membrane Association of Amphipathic Neurotransmitters

    Neuroscience

    (2018)
  • A.K. Dunker

    Intrinsically disordered protein

    J. Mol. Graph. Model.

    (2001)
  • R. Sarroukh et al.

    ATR-FTIR: a “rejuvenated” tool to investigate amyloid proteins

    Biochim. Biophys. Acta BBA

    (2013)
  • A. Schramm

    An arsenal of methods for the experimental characterization of intrinsically disordered proteins – how to choose and combine them?

    Arch. Biochem. Biophys.

    (2019)
  • M.D. Watson et al.

    Coupling chemical biology and vibrational spectroscopy for studies of amyloids in vitro and in cells

    Curr. Opin. Chem. Biol.

    (2021)
  • D. Eliezer

    Biophysical characterization of intrinsically disordered proteins

    Curr. Opin. Struct. Biol.

    (2009)
  • R. Konrat

    NMR contributions to structural dynamics studies of intrinsically disordered proteins

    J. Magn. Reson.

    (2014)
  • A.G. Kikhney et al.

    A practical guide to small angle X-ray scattering (SAXS) of flexible and intrinsically disordered proteins

    FEBS Lett.

    (2015)
  • P. Ragonis-Bachar et al.

    Functional and pathological amyloid structures in the eyes of 2020 cryo-EM

    Curr. Opin. Struct. Biol.

    (2021)
  • H. LeVine

    Quantification of β-sheet amyloid fibril structures with thioflavin T

    Methods Enzymol.

    (1999)
  • J. Adamcik et al.

    Study of amyloid fibrils via atomic force microscopy

    Curr. Opin. Colloid Interface Sci.

    (2012)
  • V. Martorana

    Amyloid jams: mechanical and dynamical properties of an amyloid fibrillar network

    Biophys. Chem.

    (2019)
  • V.N. Uversky

    Intrinsically disordered proteins and their “mysterious” (Meta)physics

    Front. Phys.

    (2019)
  • J.A. Drake et al.

    Physical chemistry of the protein backbone: enabling the mechanisms of intrinsic protein disorder

    J. Phys. Chem. B

    (2020)
  • M. Lella et al.

    Metamorphic proteins: emergence of dual protein folds from one primary sequence

    Biochemistry

    (2017)
  • P.E. Wright et al.

    Intrinsically disordered proteins in cellular signalling and regulation

    Nat. Rev. Mol. Cell Biol.

    (2015)
  • D. Milardi

    Proteostasis of islet amyloid polypeptide: A molecular perspective of risk factors and protective strategies for type II diabetes

    Chem. Rev.

    (2021)
  • P.H. Nguyen

    Amyloid oligomers: A joint experimental/computational perspective on Alzheimer’s disease, Parkinson’s disease, type II diabetes, and amyotrophic lateral sclerosis

    Chem. Rev.

    (2021)
  • A. Rauk

    The chemistry of Alzheimer’s disease

    Chem. Soc. Rev.

    (2009)
  • M. Pannuzzo

    Beta-amyloid pore linked to controlled calcium influx into the cell: A new paradigm for Alzheimer’s disease

    Alzheimers Dement.

    (2021)
  • E. Maries et al.

    The role of α-synuclein in Parkinson’s disease: insights from animal models

    Nat. Rev. Neurosci.

    (2003)
  • R.M. Meade et al.

    Alpha-synuclein structure and Parkinson’s disease – lessons and emerging principles

    Mol. Neurodegener.

    (2019)
  • B.L. Silver

    The Physical Chemistry of Membranes: An Introduction to the Structure and Dynamics of Biological Membranes

    (2013)
  • M. Pappalardo et al.

    Phase behaviour of polymer-grafted DPPC membranes for drug delivery systems design

    J. Therm. Anal. Calorim.

    (2005)
  • A. Raudino et al.

    Thermal expansion and compressibility coefficients of phospholipid vesicles: experimental determination and theoretical modeling

    J. Phys. Chem.

    (1990)
  • F. Chiti et al.

    Protein misfolding, amyloid formation, and human disease: A summary of progress over the last decade

    Annu. Rev. Biochem.

    (2017)
  • D.J. Selkoe et al.

    The amyloid hypothesis of Alzheimer’s disease at 25 years

    EMBO Mol. Med.

    (2016)
  • C. La Rosa

    Symmetry-breaking transitions in the early steps of protein self-assembly

    Eur. Biophys. J.

    (2020)
  • M.F.M. Sciacca

    Are fibril growth and membrane damage linked processes? An experimental and computational study of IAPP 12–18 and IAPP 21–27 peptides

    New J. Chem.

    (2010)
  • J.R. Brender et al.

    Membrane disruption and early events in the aggregation of the diabetes related peptide IAPP from a molecular perspective

    Acc. Chem. Res.

    (2012)
  • S. Scalisi

    Self-assembling pathway of HiApp fibrils within lipid bilayers

    ChemBioChem

    (2010)
  • C. La Rosa et al.

    Lipid-assisted protein transport: A diffusion-reaction model supported by kinetic experiments and molecular dynamics simulations

    J. Chem. Phys.

    (2016)
  • F. Scollo

    Phospholipids critical micellar concentrations trigger different mechanisms of intrinsically disordered proteins interaction with model membranes

    J. Phys. Chem. Lett.

    (2018)
  • M.F. Sciacca

    Lipid-chaperone hypothesis: A common molecular mechanism of membrane disruption by intrinsically disordered proteins

    ACS Chem. Neurosci.

    (2020)

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