Amyloid Ion Channels: a Common Structural Link for Protein-misfolding Disease

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2005 Jul 16

PMID 16020533

Citations 374

Authors

Arjan Quist

Ivo Doudevski

Hai Lin

Rushana Azimova

Douglas Ng

Blas Frangione

Bruce Kagan

Jorge Ghiso

Ratnesh Lal

Affiliations

Soon will be listed here.

Abstract

Protein conformational diseases, including Alzheimer's, Huntington's, and Parkinson's diseases, result from protein misfolding, giving a distinct fibrillar feature termed amyloid. Recent studies show that only the globular (not fibrillar) conformation of amyloid proteins is sufficient to induce cellular pathophysiology. However, the 3D structural conformations of these globular structures, a key missing link in designing effective prevention and treatment, remain undefined as of yet. By using atomic force microscopy, circular dichroism, gel electrophoresis, and electrophysiological recordings, we show here that an array of amyloid molecules, including amyloid-beta(1-40), alpha-synuclein, ABri, ADan, serum amyloid A, and amylin undergo supramolecular conformational change. In reconstituted membranes, they form morphologically compatible ion-channel-like structures and elicit single ion-channel currents. These ion channels would destabilize cellular ionic homeostasis and hence induce cell pathophysiology and degeneration in amyloid diseases.

Citing Articles

The p3 peptides (Aβ) rapidly form amyloid fibrils that cross-seed with full-length Aβ.

Tian Y, Torres-Flores A, Shang Q, Zhang H, Khursheed A, Tahirbegi B Nat Commun. 2025; 16(1):2040.

PMID: 40016209 PMC: 11868391. DOI: 10.1038/s41467-025-57341-4.

Should We Consider Neurodegeneration by Itself or in a Triangulation with Neuroinflammation and Demyelination? The Example of Multiple Sclerosis and Beyond.

Perdaens O, van Pesch V Int J Mol Sci. 2024; 25(23.

PMID: 39684351 PMC: 11641818. DOI: 10.3390/ijms252312637.

Modulation of Biological Membranes Using Small-Molecule Compounds to Counter Toxicity Caused by Amyloidogenic Proteins.

Seychell R, El Saghir A, Vassallo N Membranes (Basel). 2024; 14(11).

PMID: 39590617 PMC: 11596372. DOI: 10.3390/membranes14110231.

Pore Formation by Amyloid-like Peptides: Effects of the Nonpolar-Polar Sequence Pattern.

Rangubpit W, Sungted S, Wong-Ekkabut J, Distaffen H, Nilsson B, Dias C ACS Chem Neurosci. 2024; 15(18):3354-3362.

PMID: 39172951 PMC: 11443323. DOI: 10.1021/acschemneuro.4c00333.

Oligomer Formation by Physiologically Relevant C-Terminal Isoforms of Amyloid -Protein.

Pandey R, Urbanc B Biomolecules. 2024; 14(7).

PMID: 39062488 PMC: 11274879. DOI: 10.3390/biom14070774.

References

Green J, Kreplak L, Goldsbury C, Blatter X, Stolz M, Cooper G . Atomic force microscopy reveals defects within mica supported lipid bilayers induced by the amyloidogenic human amylin peptide. J Mol Biol. 2004; 342(3):877-87. DOI: 10.1016/j.jmb.2004.07.052. View

Hirakura Y, Carreras I, Sipe J, Kagan B . Channel formation by serum amyloid A: a potential mechanism for amyloid pathogenesis and host defense. Amyloid. 2002; 9(1):13-23. DOI: 10.3109/13506120209072440. View

Curtain C, Ali F, Smith D, Bush A, Masters C, Barnham K . Metal ions, pH, and cholesterol regulate the interactions of Alzheimer's disease amyloid-beta peptide with membrane lipid. J Biol Chem. 2002; 278(5):2977-82. DOI: 10.1074/jbc.M205455200. View

Kourie J, Henry C . Ion channel formation and membrane-linked pathologies of misfolded hydrophobic proteins: the role of dangerous unchaperoned molecules. Clin Exp Pharmacol Physiol. 2002; 29(9):741-53. DOI: 10.1046/j.1440-1681.2002.03737.x. View

Walsh D, Klyubin I, Fadeeva J, Cullen W, Anwyl R, Wolfe M . Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo. Nature. 2002; 416(6880):535-9. DOI: 10.1038/416535a. View

Etcheberrigaray R, Ito E, Kim C, Alkon D . Soluble beta-amyloid induction of Alzheimer's phenotype for human fibroblast K+ channels. Science. 1994; 264(5156):276-9. DOI: 10.1126/science.8146663. View

Dobson C . Protein folding and misfolding. Nature. 2003; 426(6968):884-90. DOI: 10.1038/nature02261. View

Kagan B . Electrophysiologic properties of channels induced by Abeta25-35 in planar lipid bilayers. Peptides. 2002; 23(7):1215-28. DOI: 10.1016/s0196-9781(02)00057-8. View

Zhu Y, Lin H, Lal R . Fresh and nonfibrillar amyloid beta protein(1-40) induces rapid cellular degeneration in aged human fibroblasts: evidence for AbetaP-channel-mediated cellular toxicity. FASEB J. 2000; 14(9):1244-54. DOI: 10.1096/fasebj.14.9.1244. View

10.

Srinivasan R, Jones E, Liu K, Ghiso J, Marchant R, Zagorski M . pH-dependent amyloid and protofibril formation by the ABri peptide of familial British dementia. J Mol Biol. 2003; 333(5):1003-23. DOI: 10.1016/j.jmb.2003.09.001. View

11.

Bucciantini M, Giannoni E, Chiti F, Baroni F, Formigli L, Zurdo J . Inherent toxicity of aggregates implies a common mechanism for protein misfolding diseases. Nature. 2002; 416(6880):507-11. DOI: 10.1038/416507a. View

12.

Lin H, Zhu Y, Lal R . Amyloid beta protein (1-40) forms calcium-permeable, Zn2+-sensitive channel in reconstituted lipid vesicles. Biochemistry. 1999; 38(34):11189-96. DOI: 10.1021/bi982997c. View

13.

Mirzabekov T, Lin M, Kagan B . Pore formation by the cytotoxic islet amyloid peptide amylin. J Biol Chem. 1996; 271(4):1988-92. DOI: 10.1074/jbc.271.4.1988. View

14.

Lashuel H, Hartley D, Petre B, Walz T, Lansbury Jr P . Neurodegenerative disease: amyloid pores from pathogenic mutations. Nature. 2002; 418(6895):291. DOI: 10.1038/418291a. View

15.

Selkoe D . Folding proteins in fatal ways. Nature. 2003; 426(6968):900-4. DOI: 10.1038/nature02264. View

16.

Ding T, Lee S, Rochet J, Lansbury Jr P . Annular alpha-synuclein protofibrils are produced when spherical protofibrils are incubated in solution or bound to brain-derived membranes. Biochemistry. 2002; 41(32):10209-17. DOI: 10.1021/bi020139h. View

17.

Kourie J, Shorthouse A . Properties of cytotoxic peptide-formed ion channels. Am J Physiol Cell Physiol. 2000; 278(6):C1063-87. DOI: 10.1152/ajpcell.2000.278.6.C1063. View

18.

Rhee S, Quist A, Lal R . Amyloid beta protein-(1-42) forms calcium-permeable, Zn2+-sensitive channel. J Biol Chem. 1998; 273(22):13379-82. DOI: 10.1074/jbc.273.22.13379. View

19.

Kawahara M, Kuroda Y, Arispe N, Rojas E . Alzheimer's beta-amyloid, human islet amylin, and prion protein fragment evoke intracellular free calcium elevations by a common mechanism in a hypothalamic GnRH neuronal cell line. J Biol Chem. 2000; 275(19):14077-83. DOI: 10.1074/jbc.275.19.14077. View

20.

Revesz T, Ghiso J, Lashley T, Plant G, Rostagno A, Frangione B . Cerebral amyloid angiopathies: a pathologic, biochemical, and genetic view. J Neuropathol Exp Neurol. 2003; 62(9):885-98. DOI: 10.1093/jnen/62.9.885. View