title: Disruption of endocytic transport by transthyretin aggregates.
abstract: The cytotoxicity of amyloidogenic proteins such as transthyretin (TTR) has implications for neurodegeneration and other pathologies, but is not well understood. In the current study, potential effects of misfolded, aggregated TTRs (agTTR) upon a major cell membrane function-endocytosis-were assessed. Internalization of transferrin (Tf), a ligand whose receptor-mediated endocytosis is well characterized, was analyzed in different cell types after treatment with agTTR. The results indicate disruption of Tf endocytosis: 20-25% inhibition by agTTR relative to the same concentrations of normal soluble TTR, or relative to another control protein, albumin (p<0.05 for agTTR relative to controls). No statistically significant difference was observed for cell surface Tf binding between agTTR-treated and control cells. This is the first evidence for endocytic disruption by agTTR, and presents a novel cytotoxicity mechanism that may account for previously reported inhibitory effects of amyloidogenic TTR on neuronal growth.
authors.affiliation: Biomedical Physiology, BPK9625, Simon Fraser University, Burnaby, B.C., Canada; Department of Neurology, Eastern Memorial Hospital, New Taipei, Taiwan.
authors.forename: Vai Hong
authors.initials: VH
authors.lastname: Fong
authors.affiliation: Biomedical Physiology, BPK9625, Simon Fraser University, Burnaby, B.C., Canada.
authors.forename: Shaun
authors.initials: S
authors.lastname: Wong
authors.affiliation: Biomedical Physiology, BPK9625, Simon Fraser University, Burnaby, B.C., Canada. Electronic address: avvieira@sfu.ca.
authors.forename: Amandio
authors.initials: A
authors.lastname: Vieira
mesh_terms: D000818:Animals; D001681:Biological Assay; D001692:Biological Transport / Q000187:drug effects; D045744:Cell Line, Tumor; D003124:Colorimetry; D004705:Endocytosis / Q000187:drug effects*; D006801:Humans; D051379:Mice; D011228:Prealbumin / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects
chemical_list: D011228:Prealbumin
keywords: Amyloidogenic; Cell membrane; Endocytosis; Protein aggregates; Transthyretin