Amyloid ion channels: A common structural link for protein-misfolding disease

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.

Are amyloid diseases caused by protein aggregates that mimic bacterial pore-forming toxins?

“…When incorporated into artificial lipid bilayers, Ab produces uniform pore-like structures with an outer diameter of 8-12 nm and inner diameter of 2 nm (Fig. 3a, c) (Lin et al 2001 ;Quist et al 2005). These aggregates, formed at the membrane surface, resemble, pore-like aggregates formed in solution using Ab42 or the disease-associated mutant form of Ab40 (E22G) .…”

Identification of a Novel Parallel β‐Strand Conformation within Molecular Monolayer of Amyloid Peptide

“…The secondary structure conversion in protein does facilitate the amyloid‐like fibril formation that is related to the pathogenesis of amyloid diseases 2, 3. In the past few years, the oligomers of amyloid peptide have been extensively studied, and the strong evidence for the extreme polymorphism of amyloid oligomers with the cytotoxicity was provided,4 such as oligomers,5 nanopores,6 and other soluble amyloid β‐barrel. These amyloid oligomers are considered to cause serious damage to the cell 7.…”

Using model membranes for the study of amyloid beta:lipid interactions and neurotoxicity

“…Species formed early in the aggregation of non disease-related proteins can be inherently cytotoxic, suggesting that avoidance of protein aggregation is crucial for the preservation of biological function (Bucciantini et al, 2002). Altered biological function due to Ab aggregation include alteration in calcium ion homeostasis, generation of reactive oxygen species, activation of specific receptors affecting cellular homeostasis, direct disruption of membrane integrity or a combination of the afore-mentioned events (McLaurin and Chakrabartty, 1996;Quist et al, 2005;Varadarajan et al, 2000). Figure 5 depicts some of the neurotoxicity-triggering mechanisms caused by Ab-peptides.…”

“…Readers are referred to a recent review by the same authors, for an indepth discussion on the Ab ion channel-based neurodegenerative mechanism (Arispe et al, 2007). The ion channels would allow excessive calcium influx into the cell, causing destabilization of cellular ionic homeostasis and inducing cell pathophysiology and neuritic degeneration in amyloid diseases (Lin et al, 2001;Quist et al, 2005).…”

“…Mechanisms for Alzheimer's neurotoxicity through soluble oligomers, and formation of Ab aggregates and fibrils. Amyloid b is implicated in (I) binding to receptors, thus altering signal transduction systems, (II) causing cell membrane damage leading to pore formation and production of free radicals, and (III) altering ion movement through interaction (blocking, for example) with ion channels (Arispe et al, 2007;McLaurin and Chakrabartty, 1996;Quist et al, 2005;Varadarajan et al, 2000).…”