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Abstract
Light chain amyloidosis (AL amyloidosis) is a haematological disorder in which a clonal population of B cells expands and secretes enormous amounts of the immunoglobulin light chain protein. These light chains misfold and aggregate into amyloid fibrils, leading to organ dysfunction and death. We have studied the in vitro fibril formation kinetics of two patient-derived immunoglobulin light chain variable domain proteins, designated AL-09 and AL-103, in response to changes in solution conditions. Both proteins are members of the κI O18:O8 germline and therefore are highly similar in sequence, but they presented with different clinical phenotypes. We find that AL-09 forms fibrils more readily and more rapidly than AL-103 in vitro, mirroring the clinical phenotypes of the patients and suggesting a possible connection between the fibril kinetics of the disease protein and the disease progression.
| Abbreviations | ||
| AL amyloidosis | = | light chain amyloidosis |
| CD | = | circular dichroism |
| Ig | = | immunoglobulin |
| MRE | = | mean residue ellipticity |
| t50 | = | time at which fibril formation reaction is 50% complete |
| ThT | = | Thioflavin T |
| VL | = | Variable domain |
| Abbreviations | ||
| AL amyloidosis | = | light chain amyloidosis |
| CD | = | circular dichroism |
| Ig | = | immunoglobulin |
| MRE | = | mean residue ellipticity |
| t50 | = | time at which fibril formation reaction is 50% complete |
| ThT | = | Thioflavin T |
| VL | = | Variable domain |
Acknowledgements
We would like to acknowledge Dr. Roshini Abraham for the contribution of patient cDNA and members of the Ramirez-Alvarado laboratory for helpful comments on the manuscript. Funding provided by NIH GM071514 (MRA), F30DK082169 (DJM), and the generous support of patients with light chain amyloidosis and the Mayo foundation.