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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.
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https://hal.univ-lille.fr/hal-03180614
Contributeur : Lilloa Université de Lille <>
Soumis le : jeudi 25 mars 2021 - 10:53:36
Dernière modification le : vendredi 9 juillet 2021 - 11:46:05
Archivage à long terme le : : samedi 26 juin 2021 - 18:28:43

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Hirokazu Kameyama, Hiroyuki Nakajima, Kazuchika Nishitsuji, Shiho Mikawa, Kenji Uchimura, et al.. Iowa Mutant Apolipoprotein A-I (ApoA-IIowa) Fibrils Target Lysosomes. Scientific Reports, Nature Publishing Group, 2016, 6, pp.30391. ⟨10.1038/srep30391⟩. ⟨hal-03180614⟩

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