Amyloid Ion Channels: A Common Structural Link for Protein-Misfolding Disease

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...

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Published inProceedings of the National Academy of Sciences - PNAS Vol. 102; no. 30; pp. 10427 - 10432
Main Authors Quist, Arjan, Doudevski, Ivo, Lin, Hai, Azimova, Rushana, Ng, Douglas, Frangione, Blas, Kagan, Bruce, Ghiso, Jorge, Lal, Ratnesh, Petsko, Gregory A.
Format Journal Article
LanguageEnglish
Published United States National Academy of Sciences 26.07.2005
National Acad Sciences
Subjects
Alzheimers disease
Amyloid - physiology
Amyloidosis - physiopathology
Amyloids
Cell membranes
Circular Dichroism
Disease
Electrophoresis
Electrophysiology
Imaging
Ion channels
Ion Channels - physiology
Ions
Liposomes
Mica
Microscopy, Atomic Force
Molecules
Monomers
Parkinson disease
Physical Sciences
Protein Conformation
Protein Folding
Science
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Summary: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-β(1-40), α-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.
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Abbreviations: Aβ(1–40), amyloid-β(1–40); AFM, atomic force microscopy; DOPC, 1,2-dioleoyl-sn-glycero-3-phosphocholine; SAA, serum amyloid A; Tricine, N-tris(hydroxymethyl)methylglycine.
This work was presented in part at the 48th Annual Meeting of the Biophysical Society, Baltimore, February 14–18, 2004.
This paper was submitted directly (Track II) to the PNAS office.
A.Q. and I.D. contributed equally to this work.
Edited by Gregory A. Petsko, Brandeis University, Waltham, MA
To whom correspondence should be addressed. E-mail: lal@lifesci.ucsb.edu.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0502066102