Amyloid Fibrils in Eye, Heart Structurally Differ Despite Same Mutation

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by Marta Figueiredo PhD |

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The toxic transthyretin (TTR) clumps that form in people with familial amyloid polyneuropathy (FAP) caused by Val30Met, the most common disease-causing mutation, are structurally different in the eye and the heart, a study suggests.

These findings highlight the structural variability of TTR clumps between organs, even when associated with the same mutation, the researchers noted. This insight may lead to the development of new therapies.

Further studies are needed to confirm these findings and understand the underlying mechanisms for such differences.

The study, “Structural basis for transthyretin amyloid formation in vitreous body of the eye,” was published in the journal Nature Communications.

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Amyloidosis is the name of a group of rare disorders characterized by the buildup of abnormal protein deposits, called amyloid fibrils, in multiple tissues and organs, disrupting their function.

FAP is a form of hereditary TTR amyloidosis that causes damage to peripheral nerves — those found outside the brain and spinal cord — and variably affects the heart, the eyes, and other tissues.

It is caused by mutations in the TTR gene, most commonly Val30Met, that are thought to change the structure of the resulting TTR protein, preventing it from acquiring a functional shape. TTR is mainly produced in the liver.

A previous study analyzing the amyloid TTR fibrils from the heart of a FAP patient with the Val30Met mutation “provided the first insights of how natively folded TTR protein changes its shape to become incorporated into a single amyloid protofilament,” the researchers wrote.

Protofilaments, long linear strings of several TTR proteins, are the most basic units of amyloid fibrils.

However, the structure of TTR fibrils from the eye remains largely unclear, even though this organ has its own source of TTR protein, which could be associated with different misfolding and aggregation mechanisms.

To address this, a team of researchers at Umeå University, in Sweden, used a high-resolution technique, called cryogenic electron microscopy, to characterize the structure of TTR fibrils from the eye of a Swedish patient with Val30Met-associated FAP. He had both peripheral nerve and heart involvement.

Results showed that these fibrils had three forms and were comprised mainly of several protofilaments.

The three types included single protofilaments (accounting for about 23% of all fibrils), two intertwined protofilaments (about 62%), and three intertwined protofilaments (about 13%). The last two formed spirallike fibrils.

These types were found to differ both in the number of protofilaments and the periodicity of the spiral twist of the multiprotofilament fibrils. Also, the latter were formed by “a previously unobserved side-by-side intertwining of the protofilaments,” the researchers wrote.

While amyloid fibrils in the eye resembled those typically classified as type A fibrils — the most common type of TTR fibrils found in FAP patients — they differed in several parameters.

They were relatively long and varied in the number of protofilaments attached, while type A fibrils isolated from the heart and peripheral nervous system in previous studies were “relatively short with a width corresponding to the size of the single protofilament,” the team wrote.

Further high-resolution structural analysis was possible only for the most abundant fibrils, those containing two intertwined protofilaments. Findings were then compared with those previously reported for the single protofilament fibril detected in the heart of a Val30Met-associated FAP patient.

While both amyloid fibrils came from patients carrying the same mutation, they differed “in both the number and arrangement of protofilaments, and the conformation of the protein fibril in each layer of protofilaments,” the researchers wrote.

These findings highlight that the structure of the TTR protein “and its assembly into protofilaments in the type A fibrils can vary between patients carrying the same mutation,” the team wrote.

Additionally, by comparing the structure of TTR fibrils with that of soluble TTR protein, researchers were able to propose a mechanism by which TTR aggregates into a fibrillar form.

Further studies are needed to understand whether TTR fibrils’ structural variability is due to patient-specific factors or protein modifications promoted by the local environment of the organ.

“These insights may be useful for the development of new therapies against ATTR amyloid,” the researchers wrote.