title: Role of mutations in the cellular internalization of amyloidogenic light chains into cardiomyocytes.
abstract: 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.
authors: Department of Biochemistry and Molecular Biology, College of Medicine, Mayo Clinic, Rochester, Minnesota 55905, USA.
authors: Rebecca T
authors: RT
authors: Levinson
authors: Oludare O
authors: OO
authors: Olatoye
authors: Edward G
authors: EG
authors: Randles
authors: Kyle G
authors: KG
authors: Howell
authors: Ara Celi
authors: AC
authors: DiCostanzo
authors: Marina
authors: M
authors: Ramirez-Alvarado
mesh_terms: D058227:Amyloidogenic Proteins / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002264:Carboxylic Acids / Q000737:chemistry; D002478:Cells, Cultured; D007147:Immunoglobulin Light Chains / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism; D051379:Mice; D018613:Microscopy, Confocal; D008969:Molecular Sequence Data; D009154:Mutation; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism*; D017433:Protein Structure, Secondary
chemical_list: D058227:Amyloidogenic Proteins; D002264:Carboxylic Acids; D007147:Immunoglobulin Light Chains; C436864:Oregon Green 488 carboxylic acid