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Autophagy Alteration in ApoA-I Related Systemic Amyloidosis. | LitMetric

AI Article Synopsis

  • - Amyloidoses involve harmful protein misfolding that leads to organ damage and cell death, with a specific mutation in Apolipoprotein A-I (L75P) causing liver dysfunction in late onset amyloidosis.
  • - The study found that this L75P variant disrupts normal cellular processes by inhibiting autophagy, causing increased mitochondrial stress and cell death in liver cells.
  • - Restoring autophagy through drugs or enhancing a specific protein (TFEB) helped improve cell function and reduce oxidative damage, indicating potential treatment avenues for ApoA-I amyloidosis.

Article 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.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8998969PMC
http://dx.doi.org/10.3390/ijms23073498DOI Listing

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