A Brief Journey through Protein Misfolding in Transthyretin Amyloidosis (ATTR Amyloidosis)

Abstract

Transthyretin (TTR) amyloidogenesis involves the formation, aggregation, and deposition of amyloid fibrils from tetrameric TTR in different organs and tissues. While the result of amyloidoses is the accumulation of amyloid fibrils resulting in end-organ damage, the nature, and sequence of the molecular causes leading to amyloidosis may differ between the different variants. In addition, fibril accumulation and toxicity vary between different mutations. Structural changes in amyloidogenic TTR have been difficult to identify through X-ray crystallography; but nuclear magnetic resonance spectroscopy has revealed different chemical shifts in the backbone structure of mutated and wild-type TTR, resulting in diverse responses to the cellular conditions or proteolytic stress. Toxic mechanisms of TTR amyloidosis have different effects on different tissues. Therapeutic approaches have evolved from orthotopic liver transplants to novel disease-modifying therapies that stabilize TTR tetramers and gene-silencing agents like small interfering RNA and antisense oligonucleotide therapies. The underlying molecular mechanisms of the different TTR variants could be responsible for the tropisms to specific organs, the age at onset, treatment responses, or disparities in the prognosis.

The interface targeting hnRNPA2B1 regulates the repression of transthyretin against human retinal microvascular endothelial cells in high‐glucose environment

“…TTR was reported to be associated with amyloidosis diseases, which are caused by the deposition of insoluble TTR amyloid fibrils. Moreover, a number of TTR single mutants have been shown to result in misfolding and precipitation, 25 which is in accordance with our results.…”

Lessons from the first-in-human in vivo CRISPR/Cas9 editing of the TTR gene by NTLA-2001 trial in patients with transthyretin amyloidosis with cardiomyopathy

“…Recent studies suggest that ATTR-CM is responsible for 20% of heart failure (HF) cases presenting with increased myocardial wall thickening ≥14 mm 13,14 . However, data on the prevalence of ATTR-CM are limited and not well characterized 15 due to missed and delayed diagnosis 16 related to the heterogeneous clinical presentation [17][18][19][20][21][22][23][24][25] and mainly because of a lack of sensitive diagnostic modality. Advancements in nuclear cardiac imaging with technetium pyrophosphate scan are leading to a more sensitive diagnosis of ATTR-CM, without cardiac biopsy 26 .…”

Omega-3 PUFAs as a Dietary Supplement in Senile Systemic Amyloidosis

“…TTR can be responsible for several amyloidosis diseases, such as familial amyloid polyneuropathy (FAP), familiar amyloid cardiomyopathy (FAC), central nervous system amyloidosis (CNSA), and senile systematic amyloidosis (SSA) [ 36 ]. While SSA is related to wild-type TTRs (wt-TTRs), the others are associated with more than a hundred TTR point mutations [ 37 ].…”