Caspase-1 causes truncation and aggregation of the Parkinson's disease-associated protein α-synuclein

Wei Wang, Linh T T Nguyen, Christopher Burlak, Fariba Chegini, Feng Guo, Tim Chataway, Shulin Ju, Oriana S. Fisher, David W. Miller, Debajyoti Datta, Fang Wu, Chun Xiang Wu, Anuradha Landeru, James A. Wells, Mark R. Cookson, Matthew B. Boxer, Craig J. Thomas, Wei Ping Gai, Dagmar Ringe, Gregory A. PetskoQuyen Hoang

Research output: Contribution to journalArticle

56 Citations (Scopus)

Abstract

The aggregation of α-synuclein (aSyn) leading to the formation of Lewy bodies is the defining pathological hallmark of Parkinson's disease (PD). Rare familial PD-associated mutations in aSyn render it aggregation-prone; however, PD patients carrying wild type (WT) aSyn also have aggregated aSyn in Lewy bodies. The mechanisms by which WT aSyn aggregates are unclear. Here, we report that inflammation can play a role in causing the aggregation of WT aSyn. We show that activation of the inflammasome with known stimuli results in the aggregation of aSyn in a neuronal cell model of PD. The insoluble aggregates are enriched with truncated aSyn as found in Lewy bodies of the PD brain. Inhibition of the inflammasome enzyme caspase-1 by chemical inhibition or genetic knockdown with shRNA abated aSyn truncation. In vitro characterization confirmed that caspase-1 directly cleaves aSyn, generating a highly aggregation-prone species. The truncation-induced aggregation of aSyn is toxic to neuronal culture, and inhibition of caspase-1 by shRNA or a specific chemical inhibitor improved the survival of a neuronal PD cell model. This study provides a molecular link for the role of inflammation in aSyn aggregation, and perhaps in the pathogenesis of sporadic PD as well.

Original languageEnglish (US)
Pages (from-to)9587-9592
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume113
Issue number34
DOIs
StatePublished - Aug 23 2016

Fingerprint

Synucleins
Caspase 1
Parkinson Disease
Inflammasomes
Lewy Bodies
Small Interfering RNA
Parkinson Disease Associated Proteins
Inflammation
Poisons

Keywords

  • Aggregation
  • Caspase
  • Inflammasome
  • Parkinson's disease
  • Synuclein

ASJC Scopus subject areas

  • General

Cite this

Caspase-1 causes truncation and aggregation of the Parkinson's disease-associated protein α-synuclein. / Wang, Wei; Nguyen, Linh T T; Burlak, Christopher; Chegini, Fariba; Guo, Feng; Chataway, Tim; Ju, Shulin; Fisher, Oriana S.; Miller, David W.; Datta, Debajyoti; Wu, Fang; Wu, Chun Xiang; Landeru, Anuradha; Wells, James A.; Cookson, Mark R.; Boxer, Matthew B.; Thomas, Craig J.; Gai, Wei Ping; Ringe, Dagmar; Petsko, Gregory A.; Hoang, Quyen.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 113, No. 34, 23.08.2016, p. 9587-9592.

Research output: Contribution to journalArticle

Wang, W, Nguyen, LTT, Burlak, C, Chegini, F, Guo, F, Chataway, T, Ju, S, Fisher, OS, Miller, DW, Datta, D, Wu, F, Wu, CX, Landeru, A, Wells, JA, Cookson, MR, Boxer, MB, Thomas, CJ, Gai, WP, Ringe, D, Petsko, GA & Hoang, Q 2016, 'Caspase-1 causes truncation and aggregation of the Parkinson's disease-associated protein α-synuclein', Proceedings of the National Academy of Sciences of the United States of America, vol. 113, no. 34, pp. 9587-9592. https://doi.org/10.1073/pnas.1610099113
Wang, Wei ; Nguyen, Linh T T ; Burlak, Christopher ; Chegini, Fariba ; Guo, Feng ; Chataway, Tim ; Ju, Shulin ; Fisher, Oriana S. ; Miller, David W. ; Datta, Debajyoti ; Wu, Fang ; Wu, Chun Xiang ; Landeru, Anuradha ; Wells, James A. ; Cookson, Mark R. ; Boxer, Matthew B. ; Thomas, Craig J. ; Gai, Wei Ping ; Ringe, Dagmar ; Petsko, Gregory A. ; Hoang, Quyen. / Caspase-1 causes truncation and aggregation of the Parkinson's disease-associated protein α-synuclein. In: Proceedings of the National Academy of Sciences of the United States of America. 2016 ; Vol. 113, No. 34. pp. 9587-9592.
@article{0fc367d77a984cc6b985afc4b6dfbe21,
title = "Caspase-1 causes truncation and aggregation of the Parkinson's disease-associated protein α-synuclein",
abstract = "The aggregation of α-synuclein (aSyn) leading to the formation of Lewy bodies is the defining pathological hallmark of Parkinson's disease (PD). Rare familial PD-associated mutations in aSyn render it aggregation-prone; however, PD patients carrying wild type (WT) aSyn also have aggregated aSyn in Lewy bodies. The mechanisms by which WT aSyn aggregates are unclear. Here, we report that inflammation can play a role in causing the aggregation of WT aSyn. We show that activation of the inflammasome with known stimuli results in the aggregation of aSyn in a neuronal cell model of PD. The insoluble aggregates are enriched with truncated aSyn as found in Lewy bodies of the PD brain. Inhibition of the inflammasome enzyme caspase-1 by chemical inhibition or genetic knockdown with shRNA abated aSyn truncation. In vitro characterization confirmed that caspase-1 directly cleaves aSyn, generating a highly aggregation-prone species. The truncation-induced aggregation of aSyn is toxic to neuronal culture, and inhibition of caspase-1 by shRNA or a specific chemical inhibitor improved the survival of a neuronal PD cell model. This study provides a molecular link for the role of inflammation in aSyn aggregation, and perhaps in the pathogenesis of sporadic PD as well.",
keywords = "Aggregation, Caspase, Inflammasome, Parkinson's disease, Synuclein",
author = "Wei Wang and Nguyen, {Linh T T} and Christopher Burlak and Fariba Chegini and Feng Guo and Tim Chataway and Shulin Ju and Fisher, {Oriana S.} and Miller, {David W.} and Debajyoti Datta and Fang Wu and Wu, {Chun Xiang} and Anuradha Landeru and Wells, {James A.} and Cookson, {Mark R.} and Boxer, {Matthew B.} and Thomas, {Craig J.} and Gai, {Wei Ping} and Dagmar Ringe and Petsko, {Gregory A.} and Quyen Hoang",
year = "2016",
month = "8",
day = "23",
doi = "10.1073/pnas.1610099113",
language = "English (US)",
volume = "113",
pages = "9587--9592",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "34",

}

TY - JOUR

T1 - Caspase-1 causes truncation and aggregation of the Parkinson's disease-associated protein α-synuclein

AU - Wang, Wei

AU - Nguyen, Linh T T

AU - Burlak, Christopher

AU - Chegini, Fariba

AU - Guo, Feng

AU - Chataway, Tim

AU - Ju, Shulin

AU - Fisher, Oriana S.

AU - Miller, David W.

AU - Datta, Debajyoti

AU - Wu, Fang

AU - Wu, Chun Xiang

AU - Landeru, Anuradha

AU - Wells, James A.

AU - Cookson, Mark R.

AU - Boxer, Matthew B.

AU - Thomas, Craig J.

AU - Gai, Wei Ping

AU - Ringe, Dagmar

AU - Petsko, Gregory A.

AU - Hoang, Quyen

PY - 2016/8/23

Y1 - 2016/8/23

N2 - The aggregation of α-synuclein (aSyn) leading to the formation of Lewy bodies is the defining pathological hallmark of Parkinson's disease (PD). Rare familial PD-associated mutations in aSyn render it aggregation-prone; however, PD patients carrying wild type (WT) aSyn also have aggregated aSyn in Lewy bodies. The mechanisms by which WT aSyn aggregates are unclear. Here, we report that inflammation can play a role in causing the aggregation of WT aSyn. We show that activation of the inflammasome with known stimuli results in the aggregation of aSyn in a neuronal cell model of PD. The insoluble aggregates are enriched with truncated aSyn as found in Lewy bodies of the PD brain. Inhibition of the inflammasome enzyme caspase-1 by chemical inhibition or genetic knockdown with shRNA abated aSyn truncation. In vitro characterization confirmed that caspase-1 directly cleaves aSyn, generating a highly aggregation-prone species. The truncation-induced aggregation of aSyn is toxic to neuronal culture, and inhibition of caspase-1 by shRNA or a specific chemical inhibitor improved the survival of a neuronal PD cell model. This study provides a molecular link for the role of inflammation in aSyn aggregation, and perhaps in the pathogenesis of sporadic PD as well.

AB - The aggregation of α-synuclein (aSyn) leading to the formation of Lewy bodies is the defining pathological hallmark of Parkinson's disease (PD). Rare familial PD-associated mutations in aSyn render it aggregation-prone; however, PD patients carrying wild type (WT) aSyn also have aggregated aSyn in Lewy bodies. The mechanisms by which WT aSyn aggregates are unclear. Here, we report that inflammation can play a role in causing the aggregation of WT aSyn. We show that activation of the inflammasome with known stimuli results in the aggregation of aSyn in a neuronal cell model of PD. The insoluble aggregates are enriched with truncated aSyn as found in Lewy bodies of the PD brain. Inhibition of the inflammasome enzyme caspase-1 by chemical inhibition or genetic knockdown with shRNA abated aSyn truncation. In vitro characterization confirmed that caspase-1 directly cleaves aSyn, generating a highly aggregation-prone species. The truncation-induced aggregation of aSyn is toxic to neuronal culture, and inhibition of caspase-1 by shRNA or a specific chemical inhibitor improved the survival of a neuronal PD cell model. This study provides a molecular link for the role of inflammation in aSyn aggregation, and perhaps in the pathogenesis of sporadic PD as well.

KW - Aggregation

KW - Caspase

KW - Inflammasome

KW - Parkinson's disease

KW - Synuclein

UR - http://www.scopus.com/inward/record.url?scp=84983688506&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84983688506&partnerID=8YFLogxK

U2 - 10.1073/pnas.1610099113

DO - 10.1073/pnas.1610099113

M3 - Article

C2 - 27482083

AN - SCOPUS:84983688506

VL - 113

SP - 9587

EP - 9592

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 34

ER -