α2M and clusterin are molecular chaperones involved in extracellular proteostasis, but α2M has a greater affinity for aggregation-prone proteins.
Newswise — When proteins are exposed to stress like high temperature, pH changes, or oxidation, they may not fold properly, and can become damaged. This can lead to a build-up of unhealthy proteins which may cause diseases like Alzheimer's.
Our body has a process called 'proteostasis' that regulates protein networks to prevent the accumulation of misfolded or defective proteins that can harm our cells. A group of special proteins called molecular chaperones play a vital role in proteostasis by identifying misfolded proteins and either repairing them or disposing of them. However, the proteostasis process is more complicated outside the cell than inside it, and we don't fully understand how it works. A protein called alpha 2-macroglobulin (ɑ2M), found in our blood, can identify and remove defective proteins, but we don't yet know how it does this.
Dr. Eisuke Itakura and his team at Chiba University have discovered what alpha 2-macroglobulin (ɑ2M) targets for degradation and developed a new way to detect how ɑ2M breaks down targeted proteins. Their findings were published in Scientific Reports on March 28, 2023.
Dr. Itakura explains that before their study, there was no way to accurately measure the lysosomal degradation of extracellular proteins. To address this, the team developed a fluorescence internalization assay that can detect the breakdown of targeted proteins by ɑ2M within lysosomes.
The researchers created an assay to measure lysosomal degradation of extracellular proteins using α2M, which was tagged with red and green fluorescence proteins (RFP and GFP) to be detected inside cells. When the α2M-RG was internalized into lysosomes, the RFP fluorescence was detected, indicating the degradation of misfolded proteins. The assay was validated in red blood cell lysates.
The researchers also compared the substrate specificities of two extracellular chaperones, α2M and clusterin, and found that although they had overlapping functions, their pathways were not redundant. They found that α2M targeted defective proteins more prone to aggregation, suggesting that different extracellular chaperones work together to protect the body from the range of misfolded proteins that may be present. This supports the theory that a variety of extracellular chaperones cooperate to protect us from different misfolded proteins.
The long-term implications of this research are that it could lead to the development of new therapeutic strategies for diseases associated with the accumulation of misfolded proteins outside cells, such as Alzheimer's disease. Understanding how extracellular chaperones like alpha 2-macroglobulin can target and degrade misfolded proteins may be useful in developing treatments that can help to clear these abnormal proteins from the body. Overall, this work could pave the way for new approaches to treating a range of protein misfolding diseases.
Dr. Itakura suggests that if a deeper understanding of the relationship between extracellular chaperones and disease is achieved, it may be possible to use blood tests to predict an individual's condition and the probability of developing a specific disease.
About Associate Professor Eisuke Itakura
Dr. Eisuke Itakura earned his Ph.D. in 2009 from the Graduate School of Science and Engineering at Saitama University. He has been at Chiba University since 2015, where he is an Associate Professor in the Department of Biology. His research interests span the role of autophagy, lysosomes, endocytosis, and the extracellular environment in the accumulation and clearance of defective proteins. He has published over 35 peer-reviewed articles since 2004.
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