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Autophagy Alteration in ApoA-I Related Systemic Amyloidosis

Rita Del Giudice1, Paola Imbimbo1, Federico Pietrocola2

  • 1Department of Chemical Sciences, University of Napoli Federico II, Complesso Universitario Monte Sant'Angelo, 80126 Napoli, Italy.

International Journal of Molecular Sciences
|April 12, 2022
PubMed

Insights

Apolipoprotein A-I (ApoA-I) amyloidosis involves protein misfolding and liver damage. This study shows inhibiting autophagy worsens ApoA-I amyloidosis, but stimulating autophagy may offer a therapeutic strategy.

Area of Science:

  • Biochemistry
  • Cell Biology
  • Genetics

Background:

  • Amyloidosis is caused by misfolded protein aggregation, leading to organ damage.
  • A specific mutation in Apolipoprotein A-I (ApoA-I; L75P-ApoA-I) causes late-onset liver amyloidosis.
  • The L75P-ApoA-I variant disrupts normal liver function through extracellular protein aggregate deposition.

Purpose of the Study:

  • To investigate the role of autophagy in L75P-ApoA-I induced liver amyloidosis.
  • To explore the cellular mechanisms underlying L75P-ApoA-I toxicity.
  • To identify potential therapeutic targets for ApoA-I amyloidosis.

Main Methods:

  • Utilized stably transfected human hepatocyte carcinoma cells expressing L75P-ApoA-I.
  • Assessed autophagic flux and cellular redox status.
  • Investigated the effects of pharmacological autophagy induction and TFEB overexpression.

Main Results:

  • L75P-ApoA-I expression inhibits the autophagic process in hepatocytes.
  • The L75P-ApoA-I variant disrupts cellular redox balance, causing mitochondrial stress and cell death.
  • Impaired autophagic flux was observed in the presence of L75P-ApoA-I.
  • Autophagy induction or TFEB overexpression restored proteostasis and reduced oxidative stress.

Conclusions:

  • Autophagy inhibition is a key feature of L75P-ApoA-I amyloidosis.
  • Pharmacological stimulation of autophagy presents a potential therapeutic avenue for treating ApoA-I amyloidosis.
  • Targeting autophagy may help restore cellular homeostasis and mitigate liver damage in this condition.
Keywords:
amyloidosisapolipoprotein A-Iapoptosisautophagy

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