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Stereotaxic Infusion of Oligomeric Amyloid-beta into the Mouse Hippocampus
Published on: June 17, 2015
Biochemical and biophysical comparison of human and mouse beta-2 microglobulin reveals the molecular determinants of
Adnane Achour1,2, Luca Broggini3, Xiao Han1,2
1Science for Life Laboratory, Department of Medicine Solna, Karolinska Institute, Solna, Sweden.
Abstract:
The molecular bases of amyloid aggregation propensity are still poorly understood, especially for proteins that display a stable folded native structure. A prototypic example is human beta-2 microglobulin (β2m), which, when accumulated in patients, gives rise to dialysis-related amyloidosis. Interestingly, although the physiologic concentration of β2m in mice is five times higher than that found in human patients, no amyloid deposits are observed in mice. Moreover, murine β2m (mβ2m) not only displays a lower amyloid propensity both in vivo and in vitro but also inhibits the aggregation of human β2m in vitro. Here, we compared human and mβ2m for their aggregation propensity, ability to form soluble oligomers, stability, three-dimensional structure and dynamics. Our results indicate that mβ2m low-aggregation propensity is due to two concomitant aspects: the low-aggregation propensity of its primary sequence combined with the absence of high-energy amyloid-competent conformations under native conditions. The identification of the specific properties determining the low-aggregation propensity of mouse β2m will help delineate the molecular risk factors which cause a folded protein to aggregate.
Insights
Murine beta-2 microglobulin (β2m) has lower amyloid aggregation propensity than human β2m. This is due to its sequence and native structure, offering insights into protein aggregation risk factors.
Area of Science:
- Biochemistry
- Structural Biology
- Protein Aggregation
Background:
- Amyloid aggregation mechanisms in folded proteins remain unclear.
- Human beta-2 microglobulin (β2m) causes dialysis-related amyloidosis.
- Mice exhibit higher physiological β2m levels but do not form amyloid.
Purpose of the Study:
- Compare aggregation propensity of human and murine β2m (mβ2m).
- Investigate structural and dynamic differences influencing aggregation.
- Identify factors conferring low aggregation risk to mβ2m.
Main Methods:
- Comparative analysis of human and mβ2m.
- Assessment of aggregation propensity in vitro and in vivo.
- Evaluation of protein stability, structure, and dynamics.
Main Results:
- mβ2m demonstrates significantly lower aggregation propensity than human β2m.
- mβ2m inhibits human β2m aggregation in vitro.
- Low aggregation propensity of mβ2m stems from its sequence and stable native state.
Conclusions:
- Mouse β2m's sequence and native conformation prevent amyloid formation.
- Understanding these properties can reveal molecular risk factors for protein aggregation.
- This research sheds light on the molecular basis of amyloidosis in folded proteins.
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