Amyloid fibril composition within hereditary Val30Met (p. Val50Met) transthyretin amyloidosis families

Suhr, Ole B.; Wixner, Jonas; Anan, Intissar; Lundgren, Hans-Erik; Wijayatunga, Priyantha; Westermark, Per; Ihse, Elisabet

doi:10.1371/journal.pone.0211983

Cited by 15 publications

(10 citation statements)

References 18 publications

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“…Moreover, in a recent study of Suhr et al, 14 out of 15 families with ATTR V30M amyloidosis exhibited a similar amyloid fibril composition within family members, independently of the age-onset disease. These observations indicate that, besides specific tissue/organ characteristics, genetic and/or epigenetic alterations may influence the amyloid fibril composition [44].…”

Section: Discussionmentioning

confidence: 96%

In Vitro and In Vivo Effects of SerpinA1 on the Modulation of Transthyretin Proteolysis

Bezerra

Niemietz

Schmidt

et al. 2021

IJMS

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Transthyretin (TTR) proteolysis has been recognized as a complementary mechanism contributing to transthyretin-related amyloidosis (ATTR amyloidosis). Accordingly, amyloid deposits can be composed mainly of full-length TTR or contain a mixture of both cleaved and full-length TTR, particularly in the heart. The fragmentation pattern at Lys48 suggests the involvement of a serine protease, such as plasmin. The most common TTR variant, TTR V30M, is susceptible to plasmin-mediated proteolysis, and the presence of TTR fragments facilitates TTR amyloidogenesis. Recent studies revealed that the serine protease inhibitor, SerpinA1, was differentially expressed in hepatocyte-like cells (HLCs) from ATTR patients. In this work, we evaluated the effects of SerpinA1 on in vitro and in vivo modulation of TTR V30M proteolysis, aggregation, and deposition. We found that plasmin-mediated TTR proteolysis and aggregation are partially inhibited by SerpinA1. Furthermore, in vivo downregulation of SerpinA1 increased TTR levels in mice plasma and deposition in the cardiac tissue of older animals. The presence of TTR fragments was observed in the heart of young and old mice but not in other tissues following SerpinA1 knockdown. Increased proteolytic activity, particularly plasmin activity, was detected in mice plasmas. Overall, our results indicate that SerpinA1 modulates TTR proteolysis and aggregation in vitro and in vivo.

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Section: Discussionmentioning

confidence: 96%

In Vitro and In Vivo Effects of SerpinA1 on the Modulation of Transthyretin Proteolysis

Bezerra

Niemietz

Schmidt

et al. 2021

IJMS

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“…6,10 Importantly, late-onset patients generally display a mixture of full-length and TTR non fibrillar fragments (Type A) while early-onset patients display only full-length TTR fibrils (Type B). 6,11,12 In addition, type amyloid fibrils have a different affinity to Congo red staining. Type A fibrils display a weaker congophilia leading to a poor possibility in detecting amyloid deposition in the biopsies of late-onset patients.…”

Section: Pathological Backgroundmentioning

confidence: 99%

The neuropathy in hereditary transthyretin amyloidosis: A narrative review

Tozza

Severi

Spina

et al. 2021

J Peripheral Nervous Sys

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Hereditary transthyretin amyloidosis (ATTRv) is a condition with adult onset, caused by mutation of the transthyretin (TTR) gene and characterized by extracellular deposition of amyloid fibrils in tissue, especially in the peripheral nervous system (PNS) and heart. PNS involvement leads to a rapidly progressive and disabling sensory-motor axonal neuropathy. Although awareness among neurologists increased in recent years thanks to new treatment options, ATTRv is frequently misdiagnosed, and thus a correct diagnosis can be delayed by several years. This review aims to draw the history and features of polyneuropathy in ATTRv based on pathological and electrophysiological correlates. We assessed original articles and case reports based on their relevance to ATTRv neuropathy and we included those appropriate for the scheme of this narrative review. Amyloid fibrils initially deposit in ganglia, causing an axonal neuropathy without amyloid deposits in distal segments (eg, sural nerve biopsy). Over time, amyloid fibrils spread along the nerves, leading to some demyelinating features in the context of severe axonal loss. This review highlights how the features of neuropathy change based on type of ATTRv (early vs late onset) and stage of disease.

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“…The disease course, lethal if left untreated after a mean of 7-10 years, is more rapid in the late-onset variety [8]. The difference between the two forms is likely explained by different types of amyloid deposits: full-length TTR forming regularly disposed fibril with high Congo red affinity in early-onset V30M (type B); a mixture of full-length and cleaved TTR fragments, with irregularly arranged fibrils showing low Congo Red affinity in late-onset V30M (type A) [14].…”

Section: Gian Maria Fabrizi Marco Luigetti Paola Mandich Anna Mazzmentioning

confidence: 99%

Hereditary transthyretin amyloidosis overview

et al. 2020

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Hereditary amyloidogenic transthyretin (ATTRv) amyloidosis is a rare autosomal dominantly inherited disorder caused by mutations in the transthyretin (TTR) gene. The pathogenetic model of ATTRv amyloidosis indicates that amyloidogenic, usually missense, mutations destabilize the native TTR favouring the dissociation of the tetramer into partially unfolded species that self-assemble into amyloid fibrils. Amyloid deposits and monomer-oligomer toxicity are the basis of multisystemic ATTRv clinical involvement. Peripheral nervous system (autonomic and somatic) and heart are the most affected sites. In the last decades, a better knowledge of pathomechanisms underlying the disease led to develop novel and promising drugs that are rapidly changing the natural history of ATTRv amyloidosis. Thus, clinicians face the challenge of timely diagnosis for addressing patients to appropriate treatment. As well, the progressive nature of ATTRv raises the issue of presymptomatic testing and risk management of carriers. The main aim of this review was to focus on what we know about ATTRv so far, from pathogenesis to clinical manifestations, diagnosis and hence patient’s monitoring and treatment, and from presymptomatic testing to management of carriers.

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Amyloid fibril composition within hereditary Val30Met (p. Val50Met) transthyretin amyloidosis families

Cited by 15 publications

References 18 publications

In Vitro and In Vivo Effects of SerpinA1 on the Modulation of Transthyretin Proteolysis

In Vitro and In Vivo Effects of SerpinA1 on the Modulation of Transthyretin Proteolysis

The neuropathy in hereditary transthyretin amyloidosis: A narrative review

Hereditary transthyretin amyloidosis overview

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