Impact of age and amyloidosis on thiol conjugation of transthyretin in hereditary transthyretin amyloidosis

Suhr, Ole B.; Svendsen, Ida Hastrup; Ohlsson, Per‐Ingvar; Lendoire, Javier; Trigo, Pedro; Tashima, Kazuhiro; Ranløv, Poul; Ando, Yukio

doi:10.3109/13506129909007325

Cited by 33 publications

(25 citation statements)

References 16 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Both forms of deposition seem to be identical with respect to primary sequence. It has been suggested that serum TTR is modified by sulfation with increasing age, and this modification could account for its propensity to deposit (Kishikawa et al, 1999;Suhr et al, 1999). Further studies are in progress in the transgenic animals to formally evaluate the possibility.…”

Section: Teng Et Almentioning

confidence: 99%

Amyloid and Nonfibrillar Deposits in Mice Transgenic for Wild-Type Human Transthyretin: A Possible Model for Senile Systemic Amyloidosis

Teng

Yin

Vidal

et al. 2001

Laboratory Investigation

View full text Add to dashboard Cite

SUMMARY:The human serum protein transthyretin (TTR) is highly fibrillogenic in vitro and is the fibril precursor in both autosomal dominant (familial amyloidotic polyneuropathy [FAP] and familial amyloidotic cardiomyopathy [FAC]) and sporadic (senile systemic amyloidosis [SSA]) forms of human cardiac amyloidosis. We have produced mouse strains transgenic for either wild-type or mutant (TTRLeu55Pro) human TTR genes. Eighty-four percent of C57Bl/6xDBA/2 mice older than 18 months, transgenic for the wild-type human TTR gene, develop TTR deposits that occur primarily in heart and kidney. In most of the animals, the deposits are nonfibrillar and non-Congophilic, but 20% of animals older than 18 months that bear the transgene have human TTR cardiac amyloid deposits identical to the lesions seen in SSA. Amino terminal amino acid sequence analysis and mass spectrometry of the major component extracted from amyloid and nonamyloid deposits revealed that both were intact human TTR monomers with no evidence of proteolysis or codeposition of murine TTR. This is the first instance in which the proteins from amyloid and nonfibrillar deposits in the same or syngeneic animals have been shown to be identical by sequence analysis. It is also the first time in any form of amyloidosis that nonfibrillar deposits have been shown to systematically occur temporally before the appearance of fibrils derived from the same precursor in the same tissues. These findings suggest, but do not prove, that the nonamyloid deposits represent a precursor of the fibril. The differences in the ultrastructure and binding properties of the deposits, despite the identical sizes and amino terminal amino acid sequences of the TTR and the dissociation of deposition and fibril formation, provide evidence that in vivo factors, perhaps associated with aging, impact on both systemic precursor deposition and amyloid fibril formation. (Lab Invest 2001, 81:385-396).

show abstract

Section: Teng Et Almentioning

confidence: 99%

Amyloid and Nonfibrillar Deposits in Mice Transgenic for Wild-Type Human Transthyretin: A Possible Model for Senile Systemic Amyloidosis

Teng

Yin

Vidal

et al. 2001

Laboratory Investigation

View full text Add to dashboard Cite

show abstract

“…Due to the very high stability of the native wild-type TTR tetramer, such analyses became possible only with the recent development of fluorescence optics for the ana- lytical ultracentrifuge (30), which are several orders of magnitude more sensitive than the existing commercial optical systems. For our studies, rTTR was produced and modified at Cys 10 by S-sulfonation and S-cysteinylation to generate the two most predominant adducts in human serum (17)(18)(19)(20). These species, as well as unmodified rTTR, were covalently bound to the amine-reactive fluorescein derivative, FITC.…”

Section: Discussionmentioning

confidence: 99%

“…It is not immediately obvious how structural instability could be conferred to wild-type TTR, but post-translational modifications are a possibility. In human serum, TTR is extensively modified at its lone cysteine residue (Cys 10 ) through mixed disulfide bonds with a number of different compounds (17)(18)(19)(20). Of these, adducts of sulfonate (S-sulfonation) and cysteine (S-cysteinylation) are generally the most common.…”

mentioning

confidence: 99%

The Modulation of Transthyretin Tetramer Stability by Cysteine 10 Adducts and the Drug Diflunisal

Kingsbury

Laue

Klimtchuk

et al. 2008

Journal of Biological Chemistry

View full text Add to dashboard Cite

Transthyretin (TTR) is normally a stable plasma protein.However, in cases of familial TTR-related amyloidosis and senile systemic amyloidosis (SSA), TTR is deposited as amyloid fibrils, leading to organ dysfunction and possibly death. The mechanism by which TTR undergoes the transition from stable, soluble precursor to insoluble amyloid fibril and the factors that promote this process are largely undetermined. Most models involve the dissociation of the native TTR tetramer as the initial step. It is largely accepted that the TTR gene mutations associated with TTR-related amyloidosis lead to the expression of variant proteins that are intrinsically unstable and prone to aggregation. It has been suggested that amyloidogenicity may be conferred to wild-type TTR (the form deposited in SSA) by chemical modification of the lone cysteine residue (Cys 10 ) through mixed disulfide bonds. S-Sulfonation and S-cysteinylation are prevalent TTR modifications physiologically, and studies have suggested their ability to modulate the structure of TTR under denaturing conditions. In the present study, we have used fluorescencedetected sedimentation velocity to determine the effect of S-sulfonate and S-cysteine on the quaternary structural stability of fluorophore-conjugated recombinant TTR under nondenaturing conditions. We determined that S-sulfonation stabilized TTR tetramer stability by a factor of 7, whereas S-cysteinylation enhanced dissociation by 2-fold with respect to the unmodified form. In addition, we report the direct observation of tetramer stabilization by the potential therapeutic compound diflunisal. Finally, as proof of concept, we report the sedimentation of TTR in serum and the qualitative assessment of the resulting data.

show abstract

“…Interestingly, of the 80 different human TTR mutants found, many are more susceptible to amyloid formation (PlantÃ-Bordeneuve and Said 2000). One specific PTM, a thiol conjugation, is found to be dependent on the age of a person and its increase is indicative of symptomatic amyloid disease (Suhr et al 1999). Thus, PTMs of TTR may be related to amyloid formation and/or toxicity.…”

Section: Ttrmentioning

confidence: 99%

Plasma biomarkers of mouse aging

Ding

Kopchick

2010

AGE

View full text Add to dashboard Cite

Normal aging is accompanied by a series of physiological changes such as gray hair, cataracts, reduced immunity, and increased susceptibility to disease. To identify novel biomarkers of normal aging, we analyzed plasma proteins of male mice longitudinally from 2 to 19 months of age. Plasma proteins were analyzed by two-dimensional gel electrophoresis and identified using mass spectrometry (MS), MS/MS and liquid chromatography MS/MS. We found that many plasma proteins exist as multiple isoforms with different masses and/or charges. Thirty-nine protein spots (corresponding to six distinct proteins) have been identified, 13 of which exhibited significant changes with age. For example, several proteins increased significantly during aging including one isoform of transthyretin, two isoforms of haptoglobin, and three isoforms of immunoglobulin kappa chain. Conversely, several proteins decreased significantly during aging including peroxiredoxin-2, serum amyloid protein A-1, and five isoforms of albumin. Identification of these proteins provides new biomarkers of normal aging in mice. If validated in humans, these biomarkers may facilitate therapeutic interventions to identify premature aging, delay aging, and/or improve healthspan of the elderly.

show abstract

Impact of age and amyloidosis on thiol conjugation of transthyretin in hereditary transthyretin amyloidosis

Cited by 33 publications

References 16 publications

Amyloid and Nonfibrillar Deposits in Mice Transgenic for Wild-Type Human Transthyretin: A Possible Model for Senile Systemic Amyloidosis

Amyloid and Nonfibrillar Deposits in Mice Transgenic for Wild-Type Human Transthyretin: A Possible Model for Senile Systemic Amyloidosis

The Modulation of Transthyretin Tetramer Stability by Cysteine 10 Adducts and the Drug Diflunisal

Plasma biomarkers of mouse aging

Contact Info

Product

Resources

About