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 Jóhannes Ísaksson; Birkir Thor Bragason; Elías Ólafsson; Astridur Palsdottir; Hakon Hakonarson

doi:10.1038/s41467-021-22120-4

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 Jóhannes Ísaksson, Birkir Thor Bragason, Elías Ólafsson, Astridur Palsdottir, Hakon Hakonarson^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

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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.

Original language	English
Article number	1827
Pages (from-to)	1827
Journal	Nature Communications
Volume	12
Issue number	1
DOIs	https://doi.org/10.1038/s41467-021-22120-4
Publication status	Published - 23 Mar 2021

Bibliographical note

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).

Other keywords

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

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10.1038/s41467-021-22120-4

s41467-021-22120-4Final published version, 1.82 MBLicence: CC BY

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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, 12(1), 1827. Article 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.",

keywords = "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",

author = "March, {Michael E.} and Alvaro Gutierrez-Uzquiza and Snorradottir, {Asbjorg Osk} and Matsuoka, {Leticia S.} and Balvis, {Noelia Fonseca} and Thorgeir Gestsson and Kenny Nguyen and Sleiman, {Patrick M.A.} and Charlly Kao and {\'I}saksson, {Helgi J{\'o}hannes} and Bragason, {Birkir Thor} and El{\'i}as {\'O}lafsson and Astridur Palsdottir and Hakon Hakonarson",

note = "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{\textquoteright}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: {\textcopyright} 2021, The Author(s).",

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doi = "10.1038/s41467-021-22120-4",

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March, ME, Gutierrez-Uzquiza, A, Snorradottir, AO, Matsuoka, LS, Balvis, NF, Gestsson, T, Nguyen, K, Sleiman, PMA, Kao, C, Ísaksson, HJ, Bragason, BT, 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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T1 - NAC blocks Cystatin C amyloid complex aggregation in a cell system and in skin of HCCAA patients

AU - March, Michael E.

AU - Gutierrez-Uzquiza, Alvaro

AU - Snorradottir, Asbjorg Osk

AU - Matsuoka, Leticia S.

AU - Balvis, Noelia Fonseca

AU - Gestsson, Thorgeir

AU - Nguyen, Kenny

AU - Sleiman, Patrick M.A.

AU - Kao, Charlly

AU - Ísaksson, Helgi Jóhannes

AU - Bragason, Birkir Thor

AU - Ólafsson, Elías

AU - Palsdottir, Astridur

AU - Hakonarson, Hakon

N1 - 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).

PY - 2021/3/23

Y1 - 2021/3/23

N2 - 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.

AB - 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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KW - Amyloidogenic Proteins/chemistry

KW - Biopsy

KW - Cerebral Amyloid Angiopathy, Familial/diet therapy

KW - Cystatin C/chemistry

KW - Cystatins/chemistry

KW - Gene Expression

KW - Glutathione/chemistry

KW - HEK293 Cells

KW - Humans

KW - Skin/drug effects

KW - Young Adult

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DO - 10.1038/s41467-021-22120-4

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AN - SCOPUS:85102896874

SN - 2041-1723

VL - 12

SP - 1827

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 1827

ER -

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

Abstract

Bibliographical note

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