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NAC blocks Cystatin C amyloid complex aggregation in a cell system and in skin of HCCAA patients

Michael E March1, Alvaro Gutierrez-Uzquiza1,2, Asbjorg Osk Snorradottir3,4

  • 1The Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.

Nature Communications
|March 24, 2021
PubMed

Insights

N-acetyl-cysteine (NAC) treatment reduced amyloid deposits in hereditary cystatin C amyloid angiopathy patients. This suggests reducing agents can target the L68Q-hCC mutation, offering a potential therapeutic strategy for this rare, inherited neurological disease.

Area of Science:

  • Neuroscience
  • Genetics
  • Biochemistry

Background:

  • Hereditary cystatin C amyloid angiopathy (HCCAA) is a rare, dominantly inherited disease.
  • It is caused by a leucine to glutamine variant (L68Q) in human cystatin C (hCC).
  • The L68Q-hCC mutation leads to amyloid deposits in brain arteries, causing severe neurological deficits and early death.

Purpose of the Study:

  • To investigate the potential of reducing agents to interfere with L68Q-hCC aggregation.
  • To assess the cellular toxicity of L68Q-hCC and the effect of reducing agents.
  • To evaluate the in vivo efficacy of N-acetyl-cysteine (NAC) in reducing L68Q-hCC deposits in patients.

Main Methods:

  • Generated cell lines expressing wild-type (WT) and L68Q-hCC to study protein aggregation.
  • Incubated L68Q-hCC with reducing agents like glutathione and NAC to observe effects on oligomers.
  • Analyzed skin biopsies from six L68Q-hCC carriers before and after NAC treatment to quantify hCC deposit reduction.

Main Results:

  • High-molecular weight complexes of L68Q-hCC were detected in cell cultures.
  • Reducing agents, including NAC, effectively broke down L68Q-hCC oligomers into monomers.
  • Five out of six treated HCCAA carriers showed a significant reduction (50-90%) in L68Q-hCC skin deposits after NAC administration.

Conclusions:

  • L68Q-hCC forms amyloidogenic aggregates that are susceptible to reduction.
  • N-acetyl-cysteine (NAC) demonstrates potential as a therapeutic agent for hereditary cystatin C amyloid angiopathy.
  • L68Q-hCC is a viable clinical target for treatment with reducing agents.

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