Studying the interaction between different amyloid (abnormal disease-causing) proteins may provide insight into the treatment of diseases such as familial amyloid polyneuropathy (FAP), an Indian study suggests.
The study, “Q-Rich Yeast Prion [PSI+] Accelerates Aggregation of Transthyretin, a Non-Q-Rich Human Protein,” appeared in the journal Frontiers in Molecular Neuroscience.
FAP is caused by mutations in the TTR gene, which result in the accumulation of the TTR protein in various organs and tissues. The mutations destabilize the protein, which is normally composed of four parts, into individual portions — monomers — with an altered structure and a higher propensity to aggregate. These aggregates may be formed by TTR monomers only or by different types of amyloid proteins, such as those involved in Alzheimer’s disease or Parkinson’s disease. This process is known as cross-seeding.
Yeast has been extensively used in the study of amyloid proteins seeding. Research showed that yeast prions (infectious proteins) with high levels of the amino acid (the building clocks of proteins) glutamine — called Q-rich — promote the aggregation of other Q-rich proteins. However, increasing evidence shows that Q-rich proteins may also interact with non-Q-rich proteins, such as the human insulin protein. In fact, recent evidence indicates that proteins do not need to share a high sequence similarity (heterologous) to interact and aggregate.
As in mammalian prion proteins, yeast prions may also have genetic variants with different aggregation abilities. One example is [PSI+] — the prion form of the yeast protein Sup35 — classified as strong or weak based on its activity and ability to form aggregates. Prion variants may interact differently with other amyloid proteins.
Interaction between different amyloid proteins is a recognized risk factor of amyloid disorders. This highlights the importance of studying how the presence of one amyloid disease may influence the development and progression of another, the authors observed. In particular, analyzing interactions between amyloid proteins may provide better insight into disease mechanisms.
Scientists created a TTR aggregation model in yeast to evaluate the interaction between monomeric human TTR and yeast prion proteins.
They observed that the engineered TTR readily formed aggregates in yeast when in acidic pH, but not at near physiological pH. This process was significantly boosted in the presence of [PSI+]. Importantly, the sequences of [PSI+] and monomeric TTR are not similar.
Results also demonstrated that different [PSI+] variants formed aggregates with TTR with diverse efficiencies. Deleting [PSI+] also reduced aggregation.
Data further showed that overproduction of the prion domain of Sup35 increased aggregation of human TTR. However, overproduction of TTR did not augment Sup35 aggregation. “Thus, it appears to be a unidirectional interaction between these two amyloid proteins,” the authors wrote.
“Our findings provide evidence for interaction of [TTR], a non-Q-rich amyloid protein with a Q-rich heterologous yeast prion protein that can be further explored for their relevance in the clinical scenario,” the scientists wrote.
They further added that similar pathways controlling aggregation in yeast and mammals represent an opportunity to study other cellular factors that may be key for amyloid diseases.