Change in variant transthyretin levels in patients with familial amyloidotic polyneuropathy type I following liver transplantation.
ABSTRACT Three patients with familial amyloidotic polyneuropathy (FAP) type I underwent liver transplantation from heart-beating cadaveric donors. Since 2 patients underwent blood transfusion during the operation, variant transthyretin (TTR) levels in the plasma did not decrease time dependently. However, in 1 patient without blood transfusion variant TTR levels decreased in a time dependent manner and plasma half life of variant TTR was calculated to be 2.1 days. Total protein, normal, and variant TTR levels in cerebrospinal fluid (CSF) remained unchanged after liver transplantation.
- SourceAvailable from: Fernando L Palhano[Show abstract] [Hide abstract]
ABSTRACT: Oculoleptomeningeal amyloidosis (OA) is a fatal and untreatable hereditary disease characterized by the accumulation of transthyretin (TTR) amyloid within the central nervous system. The mechanisms underlying the pathogenesis of OA, and in particular how amyloid triggers neuronal damage, are still unknown. Here, we show that amyloid fibrils formed by a mutant form of TTR, A25T, activate microglia, leading to the secretion of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and nitric oxide. Further, we found that A25T amyloid fibrils induce the activation of Akt, culminating in the translocation of NFκB to the nucleus of microglia. While A25T fibrils were not directly toxic to neurons, the exposure of neuronal cultures to media conditioned by fibril-activated microglia caused synapse loss that culminated in extensive neuronal death via apoptosis. Finally, intracerebroventricular (i.c.v.) injection of A25T fibrils caused microgliosis, increased brain TNF-α and IL-6 levels and cognitive deficits in mice, which could be prevented by minocycline treatment. These results indicate that A25T fibrils act as pro-inflammatory agents in OA, activating microglia and causing neuronal damage.Cell Death & Disease 01/2013; 4:e789. · 6.04 Impact Factor
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ABSTRACT: Familial amyloidotic polyneuropathy (FAP) is a hereditary amyloidosis induced by amyloidogenic transthyretin (ATTR). Because most transthyretin (TTR) in serum is synthesized by the liver, liver transplantation (LT) is today the only treatment available to halt the progression of FAP, even though LT is associated with several problems. Despite the urgent need to develop alternatives to LT, the detailed pathogenesis of FAP is still unknown; also, no model fully represents the relevant processes in patients with FAP. The induction of induced pluripotent stem (iPS) cells has allowed development of pluripotent cells specific for patients and has led to useful models of human diseases. Because of the need for a tool to elucidate the molecular pathogenesis of FAP, in this study we sought to establish heterozygous ATTR mutant iPS cells, and were successful, by using a Sendai virus vector mixture containing four transcription factors (Oct3/4, Sox2, Klf4, and c-Myc) to reprogram dermal fibroblasts derived from FAP patients. Moreover, FAP-specific iPS cells had the potential to differentiate into hepatocyte-like cells and indeed expressed ATTR. FAP-specific iPS cells demonstrated the possibility of serving as a pathological tool that will contribute to understanding the pathogenesis of FAP and development of FAP treatments.Stem Cell Research 01/2014; 12(2):574-583. · 4.47 Impact Factor
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ABSTRACT: What is known and objectiveTransthyretin (TTR) is a representative amyloidogenic protein in humans. Rate-limiting tetramer dissociation and rapid monomer misfolding and misassembly of variant TTR result in autosomal dominant familial amyloidosis. Analogous misfolding of wild-type TTR results in senile systemic amyloidosis (SSA) presenting as sporadic amyloid disease in the elderly. The objective of this review is to summarize recent progress in our understanding and treatment of TTR amyloidosis.Methods Literature searches were conducted on the topics of transthyretin, familial amyloid polyneuropathy and clinical trials, using PubMed, the United States clinical trials directory, pharmaceutical company websites and news reports. The information was collected, evaluated for relevance and quality, critically assessed and summarized.Results and discussionThe current standard first-line treatment of familial TTR amyloidosis is liver transplantation. However, large numbers of patients are not suitable transplant candidates. Recently, the clinical effects of TTR tetramer stabilizers, tafamidis and diflunisal, were demonstrated in randomized clinical trials, and tafamidis has been approved for the treatment of FAP in European countries and Japan. In addition, gene therapies with antisense oligonucleotides and small interfering RNAs are promising strategies to ameliorate TTR amyloidoses and are currently in clinical trials.What is new and conclusionsLiver transplantation to treat the familial TTR amyloidosis will likely be replaced by other less invasive therapies, such as TTR tetramer stabilizers and possibly gene therapy approaches. These newly developed therapies are expected to be effective for not only familial TTR amyloidosis but also SSA, based on their mechanisms of action.Journal of Clinical Pharmacy and Therapeutics 06/2014; 39(3). · 2.10 Impact Factor