The amyloid-cell membrane system. The interplay between the biophysical features of oligomers/fibrils and cell membrane defines amyloid toxicity

Cecchi, Cristina; Stefani, Massimo

doi:10.1016/j.bpc.2013.06.003

“…135 Thus, while these diverse proteins form very different structures in their soluble state, their fibril states are distinguished by structural commonalities, thought to be due to the ability of the primary sequence to be stabilized by hydrogen bond interactions in the polypeptide, such that β-strands of the oligomer can stack in register and be arranged perpendicular to the long axis of the ultimate fibril to generate a cross-β structure. 136-138 …”

Section: Pre-amyloid Structure and Toxicitymentioning

confidence: 99%

Proteotoxicity and Cardiac Dysfunction

McLendon

¹

,

Robbins

²

2015

Circulation Research

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Baseline physiological function of the mammalian heart is under the constant threat of environmental or intrinsic pathological insults. Cardiomyocyte proteins are thus subject to unremitting pressure to function optimally and this depends upon them assuming and maintaining proper conformation. This review explores the multiple defenses a cell may employ for its proteins to assume and maintain correct protein folding and conformation. There are multiple quality control mechanisms to ensure that nascent polypeptides are properly folded and mature proteins maintain their functional conformation. When proteins do misfold, either in the face of normal or pathologic stimuli or because of intrinsic mutations or post-translational modifications, they must either be refolded correctly or recycled. In the absence of these corrective processes, they may become toxic to the cell. Herein, we explore some of the underlying mechanisms that lead to proteotoxicity. The continued presence and chronic accumulation of misfolded or unfolded proteins can be disastrous in cardiomyocytes as these misfolded proteins can lead to aggregation or the formation of soluble peptides that are proteotoxic. This in turn leads to compromised protein quality control and precipitating a downward spiral of the cell's ability to maintain protein homeostasis. Some underlying mechanisms are discussed and the therapeutic potential of interfering with proteotoxicity in the heart is explored.

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“…The deposition of amyloid fibrils is the primary pathological feature of this group of afflictions. In recent years, however, scientific research towards the initial processes leads to fibrillation, implicated that the initial oligomeric aggregates may be the most toxic species in amyloid pathogenesis and mature fibrils may be far less pathogenic than previously thought [51,52]. These new results hint to new therapeutic strategies.…”

Section: Beyond Agelmentioning

confidence: 99%

A Nanobody‐Based Approach to Amyloid Diseases, the Gelsolin Case Study

Verhelle¹,

Gettemans²

2016

Exploring New Findings on Amyloidosis

0

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Gelsolin amyloidosis (AGel) is an autosomal-dominant inherited disease caused by point mutations in the gelsolin gene. At the protein level, these mutations result in the loss of a Ca 2+ -binding site, crucial for the correct folding and function. In the trans-Golgi network, this mutant plasma gelsolin is cleaved by furin, giving rise to a 68 kDa Cterminal fragment. When secreted in the extracellular matrix, this fragment undergoes proteolysis by MT1-MMP-like proteases, resulting in the production of 8 and 5 kDa amyloidogenic peptides. Nanobodies, the variable part of the heavy chain of heavychain antibodies, have been used as molecular chaperones for mutant plasma gelsolin and the 68 kDa C-terminal fragment in an attempt to inhibit their pathogenic proteolysis. Furthermore, these nanobodies have also been tested and applied as a 99m Tc-based imaging agent in the gelsolin amyloidosis mouse model.

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“…135 Thus, while these diverse proteins form very different structures in their soluble state, their fibril states are distinguished by structural commonalities, thought to be due to the ability of the primary sequence to be stabilized by hydrogen bond interactions in the polypeptide, such that β-strands of the oligomer can stack in register and be arranged perpendicular to the long axis of the ultimate fibril to generate a cross-β structure. [136][137][138] The Aβ oligomers characteristic of AD have been studied most intensively and their levels correlate well with disease severity. Subsequently, the monomers can reversibly undergo conformational transitions, forming dimers or trimers of low molecular weight, soluble s oligomers that, in turn, can form spherical oligomers consisting of 12-24 monomers.…”

Section: Pre-amyloid Structure and Toxicitymentioning

confidence: 99%

“…134 The propensity of oligomers to be "sticky" and exhibit detergent-like qualities has been remarked upon by a number of groups and the oligomer's ability to interact with different membrane systems has been proposed to be intrinsic to their toxicity. 138,[142][143][144][145] In the heart, membrane integrity is obviously critical for the maintenance of cell viability. Disruption of either the plasma membrane or the other vital membrane-enclosed organelles such as mitochondria or T-tubules would clearly affect cardiomyocyte function.…”

Section: Pre-amyloid Structure and Toxicitymentioning

confidence: 99%

Proteotoxicity and Cardiac Dysfunction

2013

View full text Add to dashboard Cite

Baseline physiological function of the mammalian heart is under the constant threat of environmental or intrinsic pathological insults. Cardiomyocyte proteins are thus subject to unremitting pressure to function optimally and this depends upon them assuming and maintaining proper conformation. This review explores the multiple defenses a cell may employ for its proteins to assume and maintain correct protein folding and conformation. There are multiple quality control mechanisms to ensure that nascent polypeptides are properly folded and mature proteins maintain their functional conformation. When proteins do misfold, either in the face of normal or pathologic stimuli or because of intrinsic mutations or post-translational modifications, they must either be refolded correctly or recycled. In the absence of these corrective processes, they may become toxic to the cell. Herein, we explore some of the underlying mechanisms that lead to proteotoxicity. The continued presence and chronic accumulation of misfolded or unfolded proteins can be disastrous in cardiomyocytes as these misfolded proteins can lead to aggregation or the formation of soluble peptides that are proteotoxic. This in turn leads to compromised protein quality control and precipitating a downward spiral of the cell's ability to maintain protein homeostasis. Some underlying mechanisms are discussed and the therapeutic potential of interfering with proteotoxicity in the heart is explored.

show abstract

The amyloid-cell membrane system. The interplay between the biophysical features of oligomers/fibrils and cell membrane defines amyloid toxicity

Cited by 102 publications

References 239 publications

Proteotoxicity and Cardiac Dysfunction

Proteotoxicity and Cardiac Dysfunction

A Nanobody‐Based Approach to Amyloid Diseases, the Gelsolin Case Study

Proteotoxicity and Cardiac Dysfunction

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