Pro-oxidative effects of aggregated transthyretin in human Schwannoma cells

2021

Molecules

Amyloidosis is a group of diseases that includes Alzheimer’s disease, prion diseases, transthyretin (ATTR) amyloidosis, and immunoglobulin light chain (AL) amyloidosis. The mechanism of organ dysfunction resulting from amyloidosis has been a topic of debate. This review focuses on the ultrastructure of tissue damage resulting from amyloid deposition and therapeutic insights based on the pathophysiology of amyloidosis. Studies of nerve biopsy or cardiac autopsy specimens from patients with ATTR and AL amyloidoses show atrophy of cells near amyloid fibril aggregates. In addition to the stress or toxicity attributable to amyloid fibrils themselves, the toxicity of non-fibrillar states of amyloidogenic proteins, particularly oligomers, may also participate in the mechanisms of tissue damage. The obscuration of the basement and cytoplasmic membranes of cells near amyloid fibrils attributable to an affinity of components constituting these membranes to those of amyloid fibrils may also play an important role in tissue damage. Possible major therapeutic strategies based on pathophysiology of amyloidosis consist of the following: 1) reducing or preventing the production of causative proteins; 2) preventing the causative proteins from participating in the process of amyloid fibril formation; and/or 3) eliminating already-deposited amyloid fibrils. As the development of novel disease-modifying therapies such as short interfering RNA, antisense oligonucleotide, and monoclonal antibodies is remarkable, early diagnosis and appropriate selection of treatment is becoming more and more important for patients with amyloidosis.

Section: Ultrastructure Of Tissue Damagementioning

confidence: 68%

The Ultrastructure of Tissue Damage by Amyloid Fibrils

2021

Molecules

“…In particular, the toxicity of TTR oligomers formed during the process of amyloid fibril formation has been suggested [48,56]. To support this view, studies using schwannoma or neuroblastoma cell lines demonstrated the toxic effects of nonfibrillar TTR [47,[57][58][59]. Animal models using Caenorhabditis elegans or Drosophila also demonstrated the neurotoxicity of TTR despite the absence of fibrillar amyloid deposition [59,60].…”

Section: Possible Impact Of Nonfibrillar Ttrmentioning

confidence: 99%

Transthyretin Amyloidosis: Update on the Clinical Spectrum, Pathogenesis, and Disease-Modifying Therapies

2020

Neurol Ther

ATTR amyloidosis is caused by systemic deposition of transthyretin (TTR) and comprises ATTRwt (wt for wild-type) amyloidosis, ATTRv (v for variant) amyloidosis, and acquired ATTR amyloidosis after domino liver transplantation. ATTRwt amyloidosis has classically been regarded as cardiomyopathy found in the elderly, whereas carpal tunnel syndrome has also become a major initial manifestation. The phenotypes of ATTRv amyloidosis are diverse and include neuropathy, cardiomyopathy, and oculoleptomeningeal involvement as the predominant features, depending on the mutation and age of onset. In addition to variant TTR, the deposition of wild-type TTR plays a significant role, even in patients with ATTRv amyloidosis. The formation of amyloid fibrils tends to occur in association with the basement membrane. The thickening or reduplication of the basement membrane surrounding endoneurial microvessels, which is similar to diabetic neuropathy, is observed in ATTRv amyloidosis, suggesting that common mechanisms, such as an accumulation of advanced glycation end

“…To support this view, a recent study using Caenorhabditis elegans expressing human TTR demonstrated the neurotoxicity of TTR oligomers [66]. In vitro studies using Schwannoma cell lines have also suggested the toxic effects of TTR on Schwann cells [67,68,69]. Interestingly, oligomers, rather than mature amyloid fibrils, seem to exert this toxic effect [67].…”

Section: Toxicity Of Nonfibrillar Ttrmentioning

confidence: 99%

Ultrastructure in Transthyretin Amyloidosis: From Pathophysiology to Therapeutic Insights

2019

Biomedicines

Transthyretin (TTR) amyloidosis is caused by systemic deposition of wild-type or variant amyloidogenic TTR (ATTRwt and ATTRv, respectively). ATTRwt amyloidosis has traditionally been termed senile systemic amyloidosis, while ATTRv amyloidosis has been called familial amyloid polyneuropathy. Although ATTRwt amyloidosis has classically been regarded as one of the causes of cardiomyopathy occurring in the elderly population, recent developments in diagnostic techniques have significantly expanded the concept of this disease. For example, this disease is now considered an important cause of carpal tunnel syndrome in the elderly population. The phenotypes of ATTRv amyloidosis also vary depending on the mutation and age of onset. Peripheral neuropathy usually predominates in patients from the conventional endemic foci, while cardiomyopathy or oculoleptomeningeal involvement may also become major problems in other patients. Electron microscopic studies indicate that the direct impact of amyloid fibrils on surrounding tissues leads to organ damage, whereas accumulating evidence suggests that nonfibrillar TTR, such as oligomeric TTR, is toxic, inducing neurodegeneration. Microangiopathy has been suggested to act as an initial lesion, increasing the leakage of circulating TTR. Regarding treatments, the efficacy of liver transplantation has been established for ATTRv amyloidosis patients, particularly patients with early-onset amyloidosis. Recent phase III clinical trials have shown the efficacy of TTR stabilizers, such as tafamidis and diflunisal, for both ATTRwt and ATTRv amyloidosis patients. In addition, a short interfering RNA (siRNA), patisiran, and an antisense oligonucleotide (ASO), inotersen, have been shown to be effective for ATTRv amyloidosis patients. Given their ability to significantly reduce the production of both wild-type and variant TTR in the liver, these gene-silencing drugs seem to be the optimal therapeutic option for ATTR amyloidosis. Hence, the long-term efficacy and tolerability of novel therapies, particularly siRNA and ASO, must be determined to establish an appropriate treatment program.