title: Iowa Mutant Apolipoprotein A-I (ApoA-IIowa) Fibrils Target Lysosomes.
abstract: The single amino acid mutation G26R in human apolipoprotein A-I (apoA-IIowa) is the first mutation that was associated with familial AApoA1 amyloidosis. The N-terminal fragments (amino acid residues 1-83) of apoA-I containing this mutation deposit as amyloid fibrils in patients' tissues and organs, but the mechanisms of cellular degradation and cytotoxicity have not yet been clarified. In this study, we demonstrated degradation of apoA-IIowa fibrils via the autophagy-lysosomal pathway in human embryonic kidney 293 cells. ApoA-IIowa fibrils induced an increase in lysosomal pH and the cytosolic release of the toxic lysosomal protease cathepsin B. The mitochondrial dysfunction caused by apoA-IIowa fibrils depended on cathepsin B and was ameliorated by increasing the degradation of apoA-IIowa fibrils. Thus, although apoA-IIowa fibril transport to lysosomes and fibril degradation in lysosomes may have occurred, the presence of an excess number of apoA-IIowa fibrils, more than the lysosomes could degrade, may be detrimental to cells. Our results thus provide evidence that the target of apoA-IIowa fibrils is lysosomes, and we thereby gained a novel insight into the mechanism of AApoA1 amyloidosis.
authors.affiliation: Department of Molecular Physical Pharmaceutics, Institute of Biomedical Sciences, Tokushima University Graduate School, 1-78-1 Shomachi, Tokushima 770-8505, Japan.
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Kameyama
authors.affiliation: Department of Molecular Physical Pharmaceutics, Institute of Biomedical Sciences, Tokushima University Graduate School, 1-78-1 Shomachi, Tokushima 770-8505, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Nakajima
authors.affiliation: Department of Molecular Pathology, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan.
authors.forename: Kazuchika
authors.initials: K
authors.lastname: Nishitsuji
authors.affiliation: Department of Molecular Physical Pharmaceutics, Institute of Biomedical Sciences, Tokushima University Graduate School, 1-78-1 Shomachi, Tokushima 770-8505, Japan.|Department of Biophysical Chemistry, Kyoto Pharmaceutical University, 5 Nakauchi-cho, Misasagi, Yamashina-ku, Kyoto 607-8414, Japan.
authors.forename: Shiho
authors.initials: S
authors.lastname: Mikawa
authors.affiliation: Department of Biochemistry, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Uchimura
authors.affiliation: Department of Bioanalytical Chemistry, Kobe Pharmaceutical University, 4-19-1 Motoyama-Kitamachi, Higashinada-ku, Kobe 658-8558, Japan.
authors.forename: Norihiro
authors.initials: N
authors.lastname: Kobayashi
authors.affiliation: Department of Molecular Physical Pharmaceutics, Institute of Biomedical Sciences, Tokushima University Graduate School, 1-78-1 Shomachi, Tokushima 770-8505, Japan.
authors.forename: Keiichiro
authors.initials: K
authors.lastname: Okuhira
authors.affiliation: Department of Biophysical Chemistry, Kyoto Pharmaceutical University, 5 Nakauchi-cho, Misasagi, Yamashina-ku, Kyoto 607-8414, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Saito
authors.affiliation: Department of Molecular Pathology, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan.
authors.forename: Naomi
authors.initials: N
authors.lastname: Sakashita
mesh_terms: D000199:Actins / Q000378:metabolism; D016632:Apolipoprotein A-I / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D001343:Autophagy; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000378:metabolism; D002460:Cell Line; D034281:Dynamins / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008247:Lysosomes / Q000378:metabolism*; D053078:Membrane Potential, Mitochondrial; D008928:Mitochondria / Q000378:metabolism; D008954:Models, Biological; D050505:Mutant Proteins; D066329:Protein Aggregates; D066263:Protein Aggregation, Pathological; D059748:Proteolysis; D015398:Signal Transduction
chemical_list: D000199:Actins; D016632:Apolipoprotein A-I; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D050505:Mutant Proteins; D066329:Protein Aggregates; C064972:TFEB protein, human; D034281:Dynamins