Rare diseases are often understudied, making treatments for them even rarer. One such disease is familial amyloidosis, Finnish type (FAF), so named because it was initially observed only in the Finnish population.
FAF is characterized by the abnormal build-up of a protein called amyloid in the organs, leading to blindness, paralysis and heart problems, among other symptoms. Although scientists know that FAF is associated with mutations in the gene that produces a protein called gelsolin, exactly how these mutations result in amyloid build-up has remained elusive.
Seeking the missing link, researchers at A*STAR’s Institute of Molecular and Cell Biology (IMCB) and the Bioinformatics Institute (BII) used X-ray crystallography to obtain a molecular snapshot of mutant and normal gelsolin. Unexpectedly, they observed that mutant and normal gelsolin were not only structurally similar to each other, but also functionally intact in terms of their biological activity.
Probing deeper, the group traced the root of the problem to the stability of domain-domain interactions within mutant gelsolin. Gelsolin comprises six different domains, with domain 2 containing a cleavage site for the enzyme furin. The cleavage site in domain 2 is normally blocked by domain 3.
The researchers discovered that the interaction between domains 2 and 3 was particularly weak in mutant gelsolin, which resulted in the furin cleavage site being more readily exposed. The cleavage of gelsolin by furin then sets off a chain of events leading to the build-up of amyloid.
“Furin makes the first cut in gelsolin, which leads to the progressive degradation of the gelsolin. Some of the resulting peptide fragments eventually self-assemble into amyloids which cause the symptoms of FAF,” said Robert Robinson, a Research Director at IMCB who led the study.
These findings highlight a potential strategy to control the molecular mechanisms underlying FAF onset and progression, and pave the way for better diagnostic tools to detect the disease and monitor its severity.
“Our findings tell us that we need to stabilize domain 2, which we believe can be achieved by a nanobody binding to domain 2, as we have shown in a previous study. The results also indicate that we should be looking for other mutations in gelsolin when assessing if an individual is likely to suffer FAF symptoms,” Robinson explained.
The A*STAR-affiliated researcher contributing to this research is from the Institute of Molecular and Cell Biology (IMCB) and the Bioinformatics Institute (BII).
