期刊
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
卷 23, 期 7, 页码 -出版社
MDPI
DOI: 10.3390/ijms23073498
关键词
amyloidosis; autophagy; apoptosis; apolipoprotein A-I
资金
- Karolinska Institute
- Swedish Research Council [2019-02050]
- Ramon y Cajal Program [RYC-2018-025099-I]
- Spain's Ministerio de Ciencia e Innovacion [PID2019-108827RA-I00]
- Ligue contre le Cancer (equipe labellisee)
- Agence National de la Recherche (ANR)-Projets blancs
- ANR under the frame of E-Rare-2, the ERA-Net for Research on Rare Diseases
- Association pour la recherche sur le cancer (ARC)
- Canceropole Ile-de-France
- Chancellerie des universites de Paris (Legs Poix)
- Fondation pour la Recherche Medicale (FRM)
- European Research Area Network on Cardiovascular Diseases (ERA-CVD, MINOTAUR)
- Gustave Roussy Odyssea
- European Union
- Fondation Carrefour
- High-end Foreign Expert Program in China, Institut National du Cancer (INCa) [GDW20171100085]
- Inserm (HTE)
- Institut Universitaire de France
- LeDucq Foundation
- LabEx Immuno-Oncology
- RHU Torino Lumiere
- Seerave Foundation
- SIRIC Stratified Oncology Cell DNA Repair and Tumor Immune Elimination (SOCRATE)
- CARPEM
- Swedish Research Council [2019-02050] Funding Source: Swedish Research Council
Amyloidoses are characterized by the accumulation and aggregation of misfolded proteins. In this study, a specific variant of Apolipoprotein A-I protein sequence, L75P-ApoA-I, was found to inhibit autophagy and induce excessive mitochondrial stress and cell death. Induction of autophagy or overexpression of the pro-autophagic transcription factor (TFEB) can alleviate the amyloidosis and reduce oxidative stress.
Amyloidoses are characterized by the accumulation and aggregation of misfolded proteins into fibrils in different organs, leading to cell death and consequent organ dysfunction. The specific substitution of Leu 75 for Pro in Apolipoprotein A-I protein sequence (ApoA-I; L75P-ApoA-I) results in late onset amyloidosis, where deposition of extracellular protein aggregates damages the normal functions of the liver. In this work, we describe that the autophagic process is inhibited in the presence of the L75P-ApoA-I amyloidogenic variant in stably transfected human hepatocyte carcinoma cells. The L75P-ApoA-I amyloidogenic variant alters the redox status of the cells, resulting into excessive mitochondrial stress and consequent cell death. Moreover, L75P-ApoA-I induces an impairment of the autophagic flux. Pharmacological induction of autophagy or transfection-enforced overexpression of the pro-autophagic transcription factor EB (TFEB) restores proficient proteostasis and reduces oxidative stress in these experimental settings, suggesting that pharmacological stimulation of autophagy could be a promising target to alleviate ApoA-I amyloidosis.
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