Evidence that the amyloid fibril protein in senile systemic amyloidosis is derived from normal prealbumin

Cornwell, Gibbons G.; Sletten, Knut; Johansson, Björn; Westermark, Per

doi:10.1016/0006-291x(88)90188-x

Cited by 159 publications

(101 citation statements)

References 15 publications

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“…In addition to its physiological functions, TTR is found as a main constituent of amyloid fibrils in several distinct clinical forms of amyloidoses, including familial amyloid polyneuropathy (4), familial cardiac amyloidosis (5) and sporadic senile systemic amyloidosis (SSA) (6). SSA is caused by the s elective deposition of wild-type (WT) TTR fibrils in cardiac tissue (7), affecting almost 25% of the population above 80 y of age (8,9).…”

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confidence: 99%

Heparan sulfate/heparin promotes transthyretin fibrillization through selective binding to a basic motif in the protein

Noborn

O’Callaghan

Hermansson

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Transthyretin (TTR) is a homotetrameric protein that transports thyroxine and retinol. Tetramer destabilization and misfolding of the released monomers result in TTR aggregation, leading to its deposition as amyloid primarily in the heart and peripheral nervous system. Over 100 mutations of TTR have been linked to familial forms of TTR amyloidosis. Considerable effort has been devoted to the study of TTR aggregation of these mutants, although the majority of TTR-related amyloidosis is represented by sporadic cases due to the aggregation and deposition of the otherwise stable wild-type (WT) protein. Heparan sulfate (HS) has been found as a pertinent component in a number of amyloid deposits, suggesting its participation in amyloidogenesis. This study aimed to investigate possible roles of HS in TTR aggregation. Examination of heart tissue from an elderly cardiomyopathic patient revealed substantial accumulation of HS associated with the TTR amyloid deposits. Studies demonstrated that heparin/HS promoted TTR fibrillization through selective interaction with a basic motif of TTR. The importance of HS for TTR fibrillization was illustrated in a cell model; TTR incubated with WT Chinese hamster ovary cells resulted in fibrillization of the protein, but not with HS-deficient cells (pgsD-677). The effect of heparin on TTR fibril formation was further demonstrated in a Drosophila model that overexpresses TTR. Heparin was colocalized with TTR deposits in the head of the flies reared on heparin-supplemented medium, whereas no heparin was detected in the nontreated flies. Heparin of low molecular weight (Klexane) did not demonstrate this effect.systemic amyloidosis | sulfated glycosaminoglycans | aging | heart failure

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confidence: 99%

Heparan sulfate/heparin promotes transthyretin fibrillization through selective binding to a basic motif in the protein

Noborn

O’Callaghan

Hermansson

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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“…The amyloid fibrils deposited in patients with SSA comprise exclusively wild-type (WT) TTR, while the fibrils found in patients with FAP and FAC are made up primarily of variant TTR. [13][14][15] SSA affects, to some extent, 25% of the population over 80 years of age, and primarily involves deposition of amyloid in the heart resulting in congestive heart failure. 16,17 With FAP, peripheral nerve involvement is prominent, whereas with FAC, cardiac involvement is prominent.…”

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confidence: 99%

Native state stabilization by NSAIDs inhibits transthyretin amyloidogenesis from the most common familial disease variants

Miller

Sekijima

Kelly

2004

Laboratory Investigation

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Transthyretin (TTR) tetramer dissociation and misfolding affords a monomeric amyloidogenic intermediate that misassembles into aggregates including amyloid fibrils. Amyloidogenesis of wild-type (WT) TTR causes senile systemic amyloidosis (SSA), whereas fibril formation from one of the more than 80 TTR variants leads to familial amyloidosis, typically with earlier onset than SSA. Several nonsteroidal anti-inflammatory drugs (NSAIDs) stabilize the native tetramer, strongly inhibiting TTR amyloid fibril formation in vitro. Structure-based designed NSAID analogs are even more potent amyloid inhibitors. The effectiveness of several NSAIDs, including diclofenac, diflunisal, and flufenamic acid, as well as the diclofenac analog, 2-[(3,5-dichlorophenyl) amino] benzoic acid (inhibitor 1), has been demonstrated against WT TTR amyloidogenesis. Herein, the efficacy of these compounds at preventing acid-induced fibril formation and urea-induced tetramer dissociation of the most common disease-associated TTR variants (V30M, V122I, T60A, L58H, and I84S) was evaluated. Homotetramers of these variants were employed for the studies within, realizing that the tetramers in compound heterozygote patients are normally composed of a mixture of WT and variant subunits. The most common familial TTR variants were stabilized substantially by flufenamic acid and inhibitor 1, and to a lesser extent by diflunisal, against acid-mediated fibril formation and chaotrope denaturation, suggesting that this chemotherapeutic option is viable for patients with familial transthyretin amyloidosis.

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“…1 TTR is a plasma protein responsible for carrying thyroxine in plasma and cerebrospinal fluid and indirect transportation of retinal and does so by binding to retinal binding protein (RBP) (6). The amyloidogenicity of TTR putatively causes three types of amyloid diseases: senile systemic amyloidosis (SSA), familial amyloid cardiomyopathy (FAC), and familial amyloid polyneuropathy (FAP) (7,8). The structure of TTR has been determined by high-resolution X-ray crystallography (9,10).…”

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The Sequence-Dependent Unfolding Pathway Plays a Critical Role in the Amyloidogenicity of Transthyretin

et al. 2006

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Human transthyretin (TTR) is an amyloidogenic protein whose aggregation is associated with several types of amyloid diseases. The following mechanism of TTR amyloid formation has been proposed. TTR tetramer at first dissociates into native monomers, which is the rate-limiting step in fibril formation. The monomeric species then partially unfold to form amyloidogenic intermediates that subsequently undergo a downhill self-assembly process. The amyloid deposit can be facilitated by disease-associated point mutations. However, only subtle structural differences were observed between the crystal structures of the wild type and the disease-associated variants. To investigate how single-point mutations influence the effective energy landscapes of TTR monomers, molecular dynamics (MD) simulations were performed on wild-type TTR and two pathogenic variants. Principal coordinate analysis on MD-generated ensembles has revealed multiple unfolding pathways for each protein. Amyloidogenic intermediates with the dislocated C strand-loop-D strand motif were observed only on the unfolding pathways of V30M and L55P variants and not for wild-type TTR. Our study suggests that the sequence-dependent unfolding pathway plays a crucial role in the amyloidogenicity of TTR. Analyses of side chain concerted motions indicate that pathogenic mutations on "edge strands" disrupt the delicate side chain correlated motions, which in turn may alter the sequence of unfolding events.

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Evidence that the amyloid fibril protein in senile systemic amyloidosis is derived from normal prealbumin

Cited by 159 publications

References 15 publications

Heparan sulfate/heparin promotes transthyretin fibrillization through selective binding to a basic motif in the protein

Heparan sulfate/heparin promotes transthyretin fibrillization through selective binding to a basic motif in the protein

Native state stabilization by NSAIDs inhibits transthyretin amyloidogenesis from the most common familial disease variants

The Sequence-Dependent Unfolding Pathway Plays a Critical Role in the Amyloidogenicity of Transthyretin

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