1. NAC blocks Cystatin C amyloid complex aggregation in a cell system and in skin of HCCAA patients.
- Author
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March ME, Gutierrez-Uzquiza A, Snorradottir AO, Matsuoka LS, Balvis NF, Gestsson T, Nguyen K, Sleiman PMA, Kao C, Isaksson HJ, Bragason BT, Olafsson E, Palsdottir A, and Hakonarson H
- Subjects
- Acetylcysteine administration & dosage, Acetylcysteine analogs & derivatives, Acetylcysteine chemistry, Amyloidogenic Proteins chemistry, Amyloidogenic Proteins genetics, Biopsy, Cerebral Amyloid Angiopathy, Familial drug therapy, Cerebral Amyloid Angiopathy, Familial genetics, Cystatin C chemistry, Cystatin C genetics, Cystatins chemistry, Cystatins genetics, Gene Expression, Glutathione chemistry, Glutathione pharmacology, HEK293 Cells, Humans, Skin drug effects, Skin metabolism, Young Adult, Acetylcysteine pharmacology, Amyloidogenic Proteins metabolism, Cerebral Amyloid Angiopathy, Familial diet therapy, Cystatin C metabolism, Cystatins metabolism
- 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.
- Published
- 2021
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