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.

Autophagy Alteration in ApoA‐I Related Systemic Amyloidosis / DEL GIUDICE, Rita; Imbimbo, Paola; Federico, Pietrocola; Isabelle, Martins; DE PALMA, FATIMA DOMENICA ELISA; José Manuel Bravo‐San, Pedro; Guido, Kroemer; Maiuri, MARIA CHIARA; Monti, DARIA MARIA. - In: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES. - ISSN 1661-6596. - 23:7(2022), p. 3498. [10.3390/ijms23073498]

Autophagy Alteration in ApoA‐I Related Systemic Amyloidosis

Del Giudice Rita
Primo
;
Imbimbo Paola;De Palma Fatima Domenica Elisa;Maiuri Maria Chiara;Monti Daria Maria
Ultimo
Conceptualization
2022

Abstract

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.
2022
Autophagy Alteration in ApoA‐I Related Systemic Amyloidosis / DEL GIUDICE, Rita; Imbimbo, Paola; Federico, Pietrocola; Isabelle, Martins; DE PALMA, FATIMA DOMENICA ELISA; José Manuel Bravo‐San, Pedro; Guido, Kroemer; Maiuri, MARIA CHIARA; Monti, DARIA MARIA. - In: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES. - ISSN 1661-6596. - 23:7(2022), p. 3498. [10.3390/ijms23073498]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11588/903302
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