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

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. Isaksson, Birkir Thor Bragason, Elias Olafsson, Astridur Palsdottir and Hakon Hakonarson ()
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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
Asbjorg Osk Snorradottir: Landspitali University Hospital
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
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
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
Astridur Palsdottir: Institute for Experimental Pathology at Keldur, University of Iceland
Hakon Hakonarson: The Center for Applied Genomics, The Children’s Hospital of Philadelphia

Nature Communications, 2021, vol. 12, issue 1, 1-12

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-22120-4

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