Title: | NAC blocks Cystatin C amyloid complex aggregation in a cell system and in skin of HCCAA patients |
Author: |
... 4 more authors Show all authors |
Date: | 2021-03-23 |
Language: | English |
Scope: | 1912398 |
Department: | Faculty of Medicine Clinical Laboratory Services, Diagnostics and Blood Bank Internal Medicine and Emergency Services |
Series: | Nature Communications; 12(1) |
ISSN: | 2041-1723 |
DOI: | 10.1038/s41467-021-22120-4 |
Subject: | Acetylcysteine/administration & dosage; Amyloidogenic Proteins/chemistry; Biopsy; Cerebral Amyloid Angiopathy, Familial/diet therapy; Cystatin C/chemistry; Cystatins/chemistry; Gene Expression; Glutathione/chemistry; HEK293 Cells; Humans; Skin/drug effects; Young Adult; General Physics and Astronomy; General Chemistry; General Biochemistry,Genetics and Molecular Biology |
URI: | https://hdl.handle.net/20.500.11815/3100 |
Citation:March , M E , Gutierrez-Uzquiza , A , Snorradottir , A O , Matsuoka , L S , Balvis , N F , Gestsson , T , Nguyen , K , Sleiman , P M A , Kao , C , Ísaksson , H J , Bragason , B T , Ólafsson , E , Palsdottir , A & Hakonarson , H 2021 , ' NAC blocks Cystatin C amyloid complex aggregation in a cell system and in skin of HCCAA patients ' , Nature Communications , vol. 12 , no. 1 , 1827 , pp. 1827 . https://doi.org/10.1038/s41467-021-22120-4
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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.
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Description:Funding Information: We thank all the patients involved in this study for their participation. Funding for this work was provided by an Institutional Development Fund to the Center for Applied Genomics from Children’s Hospital of Philadelphia and a sponsored Research agreement with Artic Therapeutics LLC. Funding was provided to Dr. Gutierrez-Uzquiza from Autonomous Community of Madrid (CAM). Spain. “2017-T1/BMD-5468” 2018-2020.-IP: Alvaro Gutierrez Uzquiza. Publisher Copyright: © 2021, The Author(s).
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