Proposing a minimal set of metrics and methods to predict probabilities of amyloidosis disease and onset age in individuals
| Autor: | Lee D. Hansen, Isabella James, John C. Price, Hsien-Jung L Lin, Ji Sun Park, Richard S. Criddle |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
endocrine system
Aging Amyloid Disease medicine.disease_cause Bioinformatics Models Biological Protein Aggregation Pathological Risk Assessment transthyretin Amyloid disease Protein Aggregates Protein structure Theory Article Rate of development Predictive Value of Tests Risk Factors protein folding Medicine Humans Prealbumin Genetic Predisposition to Disease Age of Onset amyloidosis Mutation Amyloid Neuropathies Familial proteostasis biology business.industry Protein Stability Amyloidosis nutritional and metabolic diseases Cell Biology medicine.disease Prognosis Transthyretin Kinetics Proteostasis Early Diagnosis Phenotype Proteolysis biology.protein business |
| Zdroj: | Aging (Albany NY) |
| ISSN: | 1945-4589 |
| Popis: | Many amyloid-driven pathologies have both genetic and stochastic components where assessing risk of disease development requires a multifactorial assessment where many of the variables are poorly understood. Risk of transthyretin-mediated amyloidosis is enhanced by age and mutation of the transthyretin (TTR) gene, but amyloidosis is not directly initiated by mutated TTR proteins. Nearly all of the 150+ known mutations increase dissociation of the homotetrameric protein structure and increase the probability of an individual developing a TTR amyloid disease late in life. TTR amyloidosis is caused by dissociated monomers that are destabilized and refold into an amyloidogenic form. Therefore, monomer concentration, monomer proteolysis rate, and structural stability are key variables that may determine the rate of development of amyloidosis. Here we develop a unifying biophysical model that quantifies the relationships among these variables in plasma and suggest the probability of an individual developing a TTR amyloid disease can be estimated. This may allow quantification of risk for amyloidosis and provide the information necessary for development of methods for early diagnosis and prevention. Given the similar observation of genetic and sporadic amyloidoses for other diseases, this model and the measurements to assess risk may be applicable to more proteins than just TTR. |
| Databáze: | OpenAIRE |
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