TY - JOUR
T1 - Role of mutations in the cellular internalization of amyloidogenic light chains into cardiomyocytes
AU - Levinson, Rebecca T.
AU - Olatoye, Oludare O.
AU - Randles, Edward G.
AU - Howell, Kyle G.
AU - DiCostanzo, Ara Celi
AU - Ramirez-Alvarado, Marina
N1 - Funding Information:
We thank Amy Cadwallader, Laura Sikkink, and Tanya Poshusta for assistance with the cloning of the expression vectors, Kristi Simmons, Eugenia Trushina, and Jonathan S. Wall for their critical reading of the manuscript, Eugene Krueger and Janey Hsu for excellent technical assistance, and the Ramirez-Alvarado laboratory for their assistance with this project. This project was supported by the National Institutes of Health R01 grant GM 071514, National Institutes of Health ARRA administrative supplement GM 071514S1, the Mayo Foundation, and the generosity of amyloidosis patients and their families.
PY - 2013
Y1 - 2013
N2 - Light chain (AL) amyloidosis is characterized by the misfolding of immunoglobulin light chains, accumulating as amyloid fibrils in vital organs. Multiple reports have indicated that amyloidogenic light chains internalize into a variety of cell types, but these studies used urine-derived proteins without indicating any protein sequence information. As a result, the role of somatic mutations in amyloidogenic protein internalization has not been yet studied. We characterized the internalization of AL-09, an AL amyloidosis protein into mouse cardiomyocytes. We also characterized the internalization of the germline protein κI O18/O8, devoid of somatic mutations, and three AL-09 restorative mutations (I34N, Q42K, and H87Y) previously characterized for their role in protein structure, stability, and amyloid formation kinetics. All proteins shared a common internalization pathway into lysosomal compartments. The proteins caused different degrees of lysosomal expansion. Oregon green (OG) labeled AL-09 showed the most rapid internalization, while OG-Q42K presented the slowest rate of internalization.
AB - Light chain (AL) amyloidosis is characterized by the misfolding of immunoglobulin light chains, accumulating as amyloid fibrils in vital organs. Multiple reports have indicated that amyloidogenic light chains internalize into a variety of cell types, but these studies used urine-derived proteins without indicating any protein sequence information. As a result, the role of somatic mutations in amyloidogenic protein internalization has not been yet studied. We characterized the internalization of AL-09, an AL amyloidosis protein into mouse cardiomyocytes. We also characterized the internalization of the germline protein κI O18/O8, devoid of somatic mutations, and three AL-09 restorative mutations (I34N, Q42K, and H87Y) previously characterized for their role in protein structure, stability, and amyloid formation kinetics. All proteins shared a common internalization pathway into lysosomal compartments. The proteins caused different degrees of lysosomal expansion. Oregon green (OG) labeled AL-09 showed the most rapid internalization, while OG-Q42K presented the slowest rate of internalization.
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U2 - 10.1038/srep01278
DO - 10.1038/srep01278
M3 - Article
C2 - 23417147
AN - SCOPUS:84874301140
SN - 2045-2322
VL - 3
JO - Scientific reports
JF - Scientific reports
M1 - 1278
ER -