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, Hakon Hakonarson

Journal: Nature communications 2021;12(1):1827

PMID: 33758187

Free Full Text on Nature Publishing Group View on PubMed

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.

Address: The Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.; Department of Biochemistry and Molecular Biology, Complutense Univeristy of Madrid, Madrid, Spain.; Department of Pathology, Landspitali University Hospital, Reykjavik, Iceland.; Faculty of Medicine, University of Iceland, Reykjavik, Iceland.; Department of Neurology, Landspitali University Hospital, Reykjavik, Iceland.; Divisions of Human Genetics and Pulmonary Medicine, Department of Pediatrics, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.; Institute for Experimental Pathology at Keldur, University of Iceland, Reykjavik, Iceland.; The Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA. [email protected].; Faculty of Medicine, University of Iceland, Reykjavik, Iceland. [email protected].; Divisions of Human Genetics and Pulmonary Medicine, Department of Pediatrics, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. [email protected].

DOI: 10.1038/s41467-021-22120-4

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https://assays.cancer.gov/non-CPTAC-1114

MeSH Terms: Acetylcysteine, Amyloidogenic Proteins, Biopsy, Cerebral Amyloid Angiopathy, Familial, Cystatin C, Cystatins, Gene Expression, Glutathione, HEK293 Cells, Humans, Skin, Young Adult