Ion channel formation and membrane‐linked pathologies of misfolded hydrophobic proteins: The role of dangerous unchaperoned molecules

Abstract

SUMMARY1. Protein-membrane interaction includes the interaction of proteins with intrinsic receptors and ion transport pathways and with membrane lipids. Several hypothetical interaction models have been reported for peptide-induced membrane destabilization, including hydrophobic clustering, electrostatic interaction, electrostatic followed by hydrophobic interaction, wedge ؋ type incorporation and hydrophobic mismatch.2. The present review focuses on the hypothesis of protein interaction with lipid membranes of those unchaperoned positively charged and misfolded proteins that have hydrophobic regions. We advance the hypothesis that protein misfolding that leads to the exposure of hydrophobic regions of proteins renders them potentially cytotoxic. Such proteins include prion, amyloid ␤ protein (A ␤ P), amylin, calcitonin, serum amyloid and C-type natriuretic peptides. These proteins have the ability to interact with lipid membranes, thereby inducing membrane damage and cell malfunction.3. We propose that the most significant mechanism of membrane damage induced by hydrophobic misfolded proteins is mediated via the formation of ion channels. The hydrophobicity based toxicity of several proteins linked to neurodegenerative pathologies is similar to those observed for antibacterial toxins and viral proteins. 4. It is hypothesized that the membrane damage induced by amyloids, antibacterial toxins and viral proteins represents a common mechanism for cell malfunction, which underlies the associated pathologies and cytotoxicity of such proteins.

Insights into the molecular basis of the differing susceptibility of varying cell types to the toxicity of amyloid aggregates

“…Interestingly, Hend cells enriched in plasma membrane cholesterol showed enhanced survival; in these, aggregate absorption to the cell membrane was reduced at levels comparable with those displayed by the most resistant cell type (HeLa). These data agree with the idea that membrane lipid composition is a key biochemical feature affecting aggregate interaction with cells, as well as affecting the type and the extent of the cell's response to their presence; they also further support the widely accepted idea that membrane derangement is an early key step in the path of cell death (Kourie and Henry, 2002;Kagan et al, 2004). In some amyloid diseases, the toxic aggregates are produced inside the cell and do not interact with the outer surface of the plasma membrane, nevertheless, our finding that toxic aggregates display reduced absorption to cell membranes enriched in cholesterol adds new information to the complex relationships between blood cholesterol and susceptibility to neurodegenerative diseases.…”

“…These comprise an imbalance of the intracellular redox status and free Ca 2+ levels (reviewed in Stefani and Dobson, 2003) together with a number of other characteristics, such as derangement of lipid homeostasis (Janciauskiene and Ahrén, 2000), interaction with membrane receptors (Mruthinti et al, 2003) and, in the case of aggregates of proteins containing poly(Q) extensions, dysregulation of the transcriptional machinery (Sakahira et al, 2002). One leading hypothesis of the molecular basis of amyloid toxicity claims that single misfolded molecules or a subpopulation of prefibrillar aggregates interacts with the cell membrane disassembling the lipid bilayer (Yip and McLaurin, 2001;Green et al, 2004); the resulting impairment of membrane permeability would then lead to an imbalance of ion homeostasis (Kourie and Henry, 2002). Indeed, modifications of ion permeability have been found in cells exposed to amyloid aggregates; in particular, alterations of the intracellular free Ca 2+ levels have been repeatedly reported (reviewed in Dobson, 2003).…”

Increased susceptibility to amyloid toxicity in familial Alzheimer's fibroblasts

“…There is evidence that protein conversion into toxic aggregates is enhanced by cellular membranes and that self-assembly on the bilayer surface is critical for membrane disruption [4]. A leading theory concerning the molecular basis of amyloid toxicity is that a sub-population of prefibrillar aggregates, assembled in pore-like fashion, interacts with cell membranes and provides them with non-specific pores leading to free Ca 2+ homeostasis imbalance [61,26,40]. The rise in free calcium is usually coupled to a marked increase in reactive oxygen species (ROS).…”

Therapeutic Targets in Extracellular Protein Deposition Diseases

“…For example, pre-fibrillar amyloid aggregates share certain structural similarities with other membrane pore-forming proteins and consequently the formation of unregulated ion channels has been proposed as a possible mechanism for their cytotoxicity [47][48][49].…”