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

Author

Listed:
  • Michael E. March

    (The Center for Applied Genomics, The Children’s Hospital of Philadelphia)

  • Alvaro Gutierrez-Uzquiza

    (The Center for Applied Genomics, The Children’s Hospital of Philadelphia
    Complutense Univeristy of Madrid)

  • Asbjorg Osk Snorradottir

    (Landspitali University Hospital
    Faculty of Medicine, University of Iceland)

  • Leticia S. Matsuoka

    (The Center for Applied Genomics, The Children’s Hospital of Philadelphia)

  • Noelia Fonseca Balvis

    (Complutense Univeristy of Madrid)

  • Thorgeir Gestsson

    (Faculty of Medicine, University of Iceland
    Landspitali University Hospital)

  • Kenny Nguyen

    (The Center for Applied Genomics, The Children’s Hospital of Philadelphia)

  • Patrick M. A. Sleiman

    (The Center for Applied Genomics, The Children’s Hospital of Philadelphia
    University of Pennsylvania)

  • Charlly Kao

    (The Center for Applied Genomics, The Children’s Hospital of Philadelphia)

  • Helgi J. Isaksson

    (Landspitali University Hospital)

  • Birkir Thor Bragason

    (Institute for Experimental Pathology at Keldur, University of Iceland)

  • Elias Olafsson

    (Faculty of Medicine, University of Iceland
    Landspitali University Hospital)

  • Astridur Palsdottir

    (Institute for Experimental Pathology at Keldur, University of Iceland)

  • Hakon Hakonarson

    (The Center for Applied Genomics, The Children’s Hospital of Philadelphia
    Faculty of Medicine, University of Iceland
    University of Pennsylvania)

Abstract

Hereditary cystatin C amyloid angiopathy is a dominantly inherited disease caused by a leucine to glutamine variant of human cystatin C (hCC). L68Q-hCC forms amyloid deposits in brain arteries associated with micro-infarcts, leading ultimately to paralysis, dementia and death in young adults. To evaluate the ability of molecules to interfere with aggregation of hCC while informing about cellular toxicity, we generated cells that produce and secrete WT and L68Q-hCC and have detected high-molecular weight complexes formed from the mutant protein. Incubations of either lysate or supernatant containing L68Q-hCC with reducing agents glutathione or N-acetyl-cysteine (NAC) breaks oligomers into monomers. Six L68Q-hCC carriers taking NAC had skin biopsies obtained to determine if hCC deposits were reduced following NAC treatment. Remarkably, ~50–90% reduction of L68Q-hCC staining was observed in five of the treated carriers suggesting that L68Q-hCC is a clinical target for reducing agents.

Suggested Citation

  • Michael E. March & Alvaro Gutierrez-Uzquiza & Asbjorg Osk Snorradottir & Leticia S. Matsuoka & Noelia Fonseca Balvis & Thorgeir Gestsson & Kenny Nguyen & Patrick M. A. Sleiman & Charlly Kao & Helgi J., 2021. "NAC blocks Cystatin C amyloid complex aggregation in a cell system and in skin of HCCAA patients," Nature Communications, Nature, vol. 12(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-22120-4
    DOI: 10.1038/s41467-021-22120-4
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