Protein Modification May Lead to Heart Problems in FAP by Promoting Aggregation of Mutant TTR, Study Says

Protein Modification May Lead to Heart Problems in FAP by Promoting Aggregation of Mutant TTR, Study Says

The addition of the amino acid homocysteine to the mutated transthyretin (TTR) protein found in patients with familial amyloid polyneuropathy may contribute to heart problems in these patients, a recent study suggests.

Specifically, this addition destabilizes and promotes the aggregation of mutant TTR protein, but it does not affect the more common variant found in healthy individuals, researchers say.

Their study, titled “S-Homocysteinylation effects on transthyretin: worsening of cardiomyopathy onset,” was published in Biochimica et Biophysica Acta (BBA) – General Subjects.

Homocysteine is a non-proteinogenic amino acid — that is, it is an amino acid not included in the protein “instructions” encoded by DNA. Instead, this amino acid is added to proteins after they are translated from what is encoded in the DNA, a process called S-homocysteinylation.

Familial amyloid polyneuropathy (FAP) is caused by mutations in the gene that encodes the protein transthyretin. These mutations lead the TTR protein to form aggregates (clumps) which in turn cause damage to cells and ultimately lead to the symptoms of the disease.

Previous research has shown that human TTR can undergo S-homocysteinylation and such an effect may be involved in disease. Moreover, “it has been proposed that accumulation of homocysteinylated proteins is an important risk factor for cardiovascular and neurodegenerative diseases,” the researchers wrote.

However, the consequences of this modification — particularly in the case of mutated TTR associated with FAP — have not been fully understood.

In the study, researchers used a series of biochemical tests to assess the effect of S-homocysteinylation of two forms of TTR: one, the wild-type, is the most common variant found in people and is not associated with any disease. The other is a mutated version called L55P-TTR, which is associated with early-onset FAP and heart disease (cardiomyopathy).

TTR normally exists as a tetramer (group of four individual units). The researchers found that S-homocysteinylation stabilized these tetramers for the wild-type TTR. However, the same modification had the opposite effect for L55P-TTR, tending to break up these units to form larger, disease-causing aggregates.

“Overall,” the researchers wrote, “these data suggest that, contrary to [wild-type]-TTR, S-homocysteinylation of L55P-TTR results in tetramer destabilization favouring the appearance of aggregation-prone low molecular weight species eventually resulting in the appearance of self-assembled large assemblies.”

Furthermore, when the researchers treated mouse heart cells in a dish with L55P-TTR, they found that greater cell death was induced (about 35% toxicity) if the protein was S-homocysteinylated than if it wasn’t (10% toxicity).

Additionally, S-homocysteinylated L55P-TTR caused significant changes in the way these cells behaved; cells treated with S-homocysteinylated L55P-TTR beat more frequently and contracted with more force, compared with unmodified L55P-TTR. These data suggest that this modification may play a role in heart problems in FAP.

“Our results could have pathophysiological [disease development] relevance, contributing to shed light into the molecular mechanisms underlying some pathological consequences described in patients affected by hyperhomocysteinemia [abnormally high level of homocysteine in the blood],” the authors said.

Marisa holds an MS in Cellular and Molecular Pathology from the University of Pittsburgh, where she studied novel genetic drivers of ovarian cancer. She specializes in cancer biology, immunology, and genetics. Marisa began working with BioNews in 2018, and has written about science and health for SelfHacked and the Genetics Society of America. She also writes/composes musicals and coaches the University of Pittsburgh fencing club.
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Margarida graduated with a BS in Health Sciences from the University of Lisbon and a MSc in Biotechnology from Instituto Superior Técnico (IST-UL). She worked as a molecular biologist research associate at a Cambridge UK-based biotech company that discovers and develops therapeutic, fully human monoclonal antibodies.
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Marisa holds an MS in Cellular and Molecular Pathology from the University of Pittsburgh, where she studied novel genetic drivers of ovarian cancer. She specializes in cancer biology, immunology, and genetics. Marisa began working with BioNews in 2018, and has written about science and health for SelfHacked and the Genetics Society of America. She also writes/composes musicals and coaches the University of Pittsburgh fencing club.
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