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Updated: Nov 2, 2025
Assays for the Degradation of Misfolded Proteins in Cells
Published on: August 28, 2016
Living with the enemy: from protein-misfolding pathologies we know, to those we want to know
Abdul-Hamid Emwas1, Mawadda Alghrably2, Manel Dhahri3
1King Abdullah University of Science and Technology, Core Labs, Thuwal, 23955-6900, Saudi Arabia.
Abstract:
Conformational diseases are caused by the aggregation of misfolded proteins. The risk for such pathologies develops years before clinical symptoms appear, and is higher in people with alpha-1 antitrypsin (AAT) polymorphisms. Thousands of people with alpha-1 antitrypsin deficiency (AATD) are underdiagnosed. Enemy-aggregating proteins may reside in these underdiagnosed AATD patients for many years before a pathology for AATD fully develops. In this perspective review, we hypothesize that the AAT protein could exert a new and previously unconsidered biological effect as an endogenous metal ion chelator that plays a significant role in essential metal ion homeostasis. In this respect, AAT polymorphism may cause an imbalance of metal ions, which could be correlated with the aggregation of amylin, tau, amyloid beta, and alpha synuclein proteins in type 2 diabetes mellitus (T2DM), Alzheimer's and Parkinson's diseases, respectively.
Insights
Alpha-1 antitrypsin (AAT) deficiency may be linked to metal ion imbalance, potentially contributing to protein misfolding diseases. This underdiagnosed condition could play a role in Alzheimer's, Parkinson's, and diabetes years before symptoms arise.
Area of Science:
- Biochemistry
- Neuroscience
- Genetics
Background:
- Conformational diseases arise from misfolded protein aggregation, with risks developing years before clinical manifestation.
- Alpha-1 antitrypsin (AAT) polymorphisms increase susceptibility to these pathologies, and AAT deficiency (AATD) is often underdiagnosed.
- Misfolded proteins may silently accumulate in underdiagnosed AATD patients long before disease onset.
Purpose of the Study:
- To propose a novel hypothesis on the biological role of AAT.
- To investigate AAT's potential function as an endogenous metal ion chelator.
- To explore the link between AAT polymorphisms, metal ion homeostasis, and protein aggregation diseases.
Main Methods:
- This is a perspective review, synthesizing existing knowledge and proposing a new hypothesis.
- The review examines the role of metal ion homeostasis in protein aggregation.
- It correlates AAT polymorphisms with potential metal ion imbalances.
Main Results:
- AAT may function as a previously unrecognized endogenous metal ion chelator.
- AAT polymorphisms could disrupt essential metal ion homeostasis.
- This disruption may correlate with the aggregation of specific proteins implicated in T2DM, Alzheimer's, and Parkinson's.
Conclusions:
- AAT's role in metal ion chelation offers a new perspective on conformational diseases.
- Underdiagnosed AATD may contribute to the development of neurodegenerative and metabolic disorders.
- Further research into AAT and metal ion interactions is warranted to understand disease pathogenesis.
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