Discovery of a Blood-Borne Scavenger Carrier That Degrades Serum Amyloid A – A New Foundation for Treating Intractable AA Amyloidosis

A research group led by Professor Eisuke Itakura at Chiba University's Graduate School of Science has discovered that the blood protein GPLD1 (Note 1) acts as a scavenger carrier that directly captures the abnormal protein 'serum amyloid A1 (SAA1)', the cause of the designated intractable disease AA amyloidosis (Note 2), transports it to lysosomes (Note 3) within cells, and leads to the degradation of SAA1 (Figure). This is the discovery of a new mechanism for maintaining extracellular protein homeostasis (proteostasis) (Note 4). This achievement makes it possible to efficiently remove SAA1, the causative protein of intractable diseases such as AA amyloidosis, and is expected to lead to applications in disease prevention and treatment.

This research result was published in the American scientific journal Life Science Alliance on June 5, 2026.

(Paper here: 10.26508/lsa.202603717)

Figure: Flow of GPLD1 degrading and removing SAA1 and heat-denatured proteins in the blood

Research Background

When inflammation occurs in our body, the protein 'serum amyloid A1 (SAA1)' rapidly increases in the blood. While this protein is normally involved in biological defense, if it accumulates excessively during chronic inflammation, it transforms into an 'abnormal protein' that adheres to organs throughout the body, causing severe dysfunction, becoming the causative agent of the intractable disease 'AA amyloidosis'.

Until now, the fundamental mechanism of how the body recognizes and cleans up this 'protein garbage accumulated outside cells' has been a major mystery. Elucidating this 'cleaning mechanism' is an indispensable step towards overcoming AA amyloidosis, which has been difficult to treat for many years.

Research Results

To identify the 'cleaner' factor that leads to the degradation of increased SAA1 in the blood, the research group searched for proteins that directly bind to SAA1. As a result, they discovered that a protein called 'GPLD1' present in the blood specifically binds to SAA1.

To analyze the role of GPLD1 in detail, the study utilized a unique 'uptake assay method' (Note 5). They found that GPLD1 forms a complex with SAA1 outside the cell, is then taken up into the cell, and is transported to the 'lysosome', the cell's degradation factory, promoting the degradation of SAA1. In other words, it plays the role of 'collecting and disposing of garbage'. Previously, GPLD1 was known as a cleavage enzyme for the lipid tether 'GPI-anchored membrane protein' that connects proteins, essentially 'scissors that only cut the tether'. This discovery reveals a new function different from this known role.

In previous studies, the research group has elucidated the existence of other 'scavenger carriers' such as 'Clusterin' and 'α2-macroglobulin' (references). When they investigated the difference in roles between GPLD1 and Clusterin this time, they found that while both lead to the degradation of heat-denatured proteins, SAA1 is degraded only by GPLD1. On the other hand, it was also clarified that amyloid β, the cause of Alzheimer's disease, is degraded only by Clusterin and GPLD1 is not involved.

Researcher's Comment

Following the discovery of Clusterin and α2-macroglobulin, this study has revealed that GPLD1 is the third 'scavenger carrier in the blood' and plays an important role in specifically targeting and degrading SAA1. Even when we simply say 'protein garbage' outside cells, their types and properties are diverse. By elucidating the mechanisms that clean the body one by one, as in this case, we aim to contribute to the establishment of new treatments with fewer side effects by selectively removing only the specific abnormal proteins that cause diseases.

Glossary

Note 1) GPLD1: Glycosylphosphatidylinositol-specific phospholipase D1 (GPLD1). A protein mainly produced in the liver and present in blood plasma. It is known as an enzyme that cleaves 'GPI-anchored membrane proteins' bound to the cell surface.

Note 2) AA amyloidosis: An intractable disease, a type of systemic amyloidosis that develops secondary to chronic inflammation. The causative protein 'amyloid A' changes into a fibrous form and deposits in organs throughout the body, causing dysfunction.

Note 3) Lysosome: One of the organelles present within cells. It has the role of degrading and processing unnecessary proteins.

Note 4) Proteostasis: The mechanism for maintaining proteins in a normal state within a living organism. It maintains normal bodily functions by degrading and removing unnecessary or abnormal proteins.

Note 5) Uptake assay method: A method for quantitative analysis using a flow cytometer (automated cell analysis and sorting device) of the amount of fluorescent protein accumulated in lysosomes after cells take up extracellular proteins labeled with fluorescence.

About the Research Project

This research was conducted with the support of the following:

[Japan Science and Technology Agency (JST)] FOREST Program JPMJFR204N

[Japan Society for the Promotion of Science (JSPS)] Grants-in-Aid for Transformative Research Areas (A) JP23H04932, Grant-in-Aid for Scientific Research (B) JP24K02018, JP20H03249, Grant-in-Aid for Scientific Research on Innovative Areas (Research in a Proposed Research Area) JP22H04634, J-PEAKS JPJS00420230002

Paper Information

Title: GPLD1 is as a scavenger carrier mediating lysosomal degradation of extracellular aberrant proteins

Authors: Mizuki Tsuchiya, Yoichiro Yagishita, Eisuke Itakura

Journal: Life Science Alliance

DOI: 10.26508/lsa.202603717

References

Press release published February 12, 2020: 'Discovery of a system for removing extracellular abnormal proteins'

Press release published March 28, 2023: 'Discovery of the role of α2-macroglobulin in degrading denatured proteins'