Abstract
BackgroundA functional link has been established between the severe neurodegenerative disorder Familial amyloidotic polyneuropathy and the enhanced propensity of the plasma protein transthyretin (TTR) to form aggregates in patients with single point mutations in the TTR gene. Previous work has led to the establishment of an experimental model based on transgenic expression of normal or mutant forms of human TTR in Drosophila flies. Remarkably, the severity of the phenotype was greater in flies that expressed a single copy than with two copies of the mutated gene.Methodology/Principal FindingsIn this study, we analyze the distribution of normal and mutant TTR in transgenic flies, and the ultrastructure of TTR-positive tissues to clarify if aggregates and/or amyloid filaments are formed. We report the formation of intracellular aggregates of 20 nm spherules and amyloid filaments in thoracic adipose tissue and in brain glia, two tissues that do not express the transgene. The formation of aggregates of nanospherules increased with age and was more considerable in flies with two copies of mutated TTR. Treatment of human neuronal cells with protein extracts prepared from TTR flies of different age showed that the extracts from older flies were less toxic than those from younger flies.Conclusions/SignificanceThese findings suggest that the uptake of TTR from the circulation and its subsequent segregation into cytoplasmic quasi-crystalline arrays of nanospherules is part of a mechanism that neutralizes the toxic effect of TTR.
Highlights
The transthyretin (TTR) amyloidoses represent a group of human diseases in which misfolded molecules of TTR aggregate and cause damage to surrounding tissues
For practical reasons we focused on the dorsal thorax, preparing samples that contained some of the major flight muscles with attached motor neurons, sensory axons, fat body, tracheae, hemocytes and epidermis
With formation of amyloidogenic aggregates and amyloid filaments have become of increasing interest due to their involvement in many debilitating disorders such as Alzheimer’s disease, Parkinson’s disease and TTR-associated amyloidoses
Summary
The transthyretin (TTR) amyloidoses represent a group of human diseases in which misfolded molecules of TTR aggregate and cause damage to surrounding tissues. TTR is one of the 27 human proteins known to be associated with local or systemic amyloidosis [5]. TTR has, an inherent propensity to assemble into insoluble amyloid fibrils, which sporadically leads to senile systemic amyloidosis (SSA) with deposits of wild-type TTR (TTRwt) mainly in the cardiac tissue late in life [8]. Familial forms of TTR-related amyloidosis are inherited in an autosomal dominant manner and arise from single point mutations in the coding sequence of the gene. A functional link has been established between the severe neurodegenerative disorder Familial amyloidotic polyneuropathy and the enhanced propensity of the plasma protein transthyretin (TTR) to form aggregates in patients with single point mutations in the TTR gene. The severity of the phenotype was greater in flies that expressed a single copy than with two copies of the mutated gene
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