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Thermal Stability Threshold for Amyloid Formation in Light Chain Amyloidosis
Department of Biochemistry and Molecular Biology, Mayo Clinic, 200 First St. SW, Rochester, MN 55905, USA
Department of Medicine (Neurology and Rheumatology), Shinshu University, 3-1-1, Asahi, Matsumoto City 390-8621, Japan
Division of Hematology, Mayo Clinic, 200 First St. SW, Rochester, MN 55905, USA
These authors contributed equally to this work.
* Author to whom correspondence should be addressed.
Received: 1 October 2013; in revised form: 25 October 2013 / Accepted: 4 November 2013 / Published: 15 November 2013
Abstract: Light chain (AL) amyloidosis is a devastating disease characterized by amyloid deposits formed by immunoglobulin light chains. Current available treatments involve conventional chemotherapy and autologous stem cell transplant. We have recently concluded a phase III trial comparing these two treatments. AL amyloidosis patients who achieve hematological complete response (CR) do not necessarily achieve organ response regardless of the treatment they received. In order to investigate the possible correlation between amyloid formation kinetics and organ response, we selected AL amyloidosis patients from the trial with kidney involvement and CR after treatment. Six patients were selected and their monoclonal immunoglobulin light chains were characterized. The proteins showed differences in their stability and their kinetics of amyloid formation. A correlation was detected at pH 7.4, showing that less stable proteins are more likely to form amyloid fibrils. AL-T03 is too unstable to form amyloid fibrils at pH 7.4. This protein was found in the only patient in the study that had organ response, suggesting that partially folded species are required for amyloid formation to occur in AL amyloidosis.
Keywords: light chain amyloidosis; immunoglobulin light chain; hematologic response; organ response; thermodynamic stability; amyloid fibril formation; partially folded states
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Poshusta, T.L.; Katoh, N.; Gertz, M.A.; Dispenzieri, A.; Ramirez-Alvarado, M. Thermal Stability Threshold for Amyloid Formation in Light Chain Amyloidosis. Int. J. Mol. Sci. 2013, 14, 22604-22617.
Poshusta TL, Katoh N, Gertz MA, Dispenzieri A, Ramirez-Alvarado M. Thermal Stability Threshold for Amyloid Formation in Light Chain Amyloidosis. International Journal of Molecular Sciences. 2013; 14(11):22604-22617.
Poshusta, Tanya L.; Katoh, Nagaaki; Gertz, Morie A.; Dispenzieri, Angela; Ramirez-Alvarado, Marina. 2013. "Thermal Stability Threshold for Amyloid Formation in Light Chain Amyloidosis." Int. J. Mol. Sci. 14, no. 11: 22604-22617.