Opin vísindi

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

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


Title: NAC blocks Cystatin C amyloid complex aggregation in a cell system and in skin of HCCAA patients
Author: March, Michael E.
Gutierrez-Uzquiza, Alvaro
Snorradottir, Asbjorg Osk
Matsuoka, Leticia S.
Balvis, Noelia Fonseca
Gestsson, Thorgeir
Nguyen, Kenny
Sleiman, Patrick M.A.
Kao, Charlly
Ísaksson, Helgi Jóhannes
... 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

Show full item record

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

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.

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).

Files in this item

This item appears in the following Collection(s)