Targeting extracellular cyclophilin a reduces neuroinflammation and extends survival in a mouse model of amyotrophic lateral sclerosis

Laura Pasetto, Silvia Pozzi, Mariachiara Castelnovo, Manuela Basso, Alvaro G. Estevez, Stefano Fumagalli, Maria Grazia De Simoni, Valeria Castellaneta, Paolo Bigini, Elena Restelli, Roberto Chiesa, Francesca Trojsi, Maria Rosaria Monsurrò, Leonardo Callea, Miroslav Malešević, Gunter Fischer, Mattia Freschi, Massimo Tortarolo, Caterina Bendotti, Valentina Bonetto

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

Neuroinflammationis amajor hallmarkof amyotrophiclateral sclerosis (ALS), whichis currentlyuntreatable. Several anti-inflammatory compounds have been evaluated in patients and in animal models of ALS, but have been proven disappointing in part because effective targets have not yet been identified. Cyclophilin A, also known as peptidylprolyl cis-/trans-isomerase A (PPIA), as a foldase is beneficial intracellularly, but extracellularly has detrimental functions. We found that extracellular PPIA is a mediator of neuroinflammation in ALS. It is a major inducer of matrix metalloproteinase 9 and is selectively toxic for motor neurons. High levels of PPIA were found in the CSF of SOD1G93A mice and rats and sporadic ALS patients, suggesting that our findings may be relevant for familial and sporadic cases. A specific inhibitor of extracellular PPIA, MM218, given at symptom onset, rescued motor neurons and extended survival in the SOD1G93A mouse model of familial ALS by 11 d. The treatment resulted in the polarization of glia toward a prohealing phenotype associated with reduced NF-κB activation, proinflammatory markers, endoplasmic reticulum stress, and insoluble phosphorylated TDP-43. Our results indicates that extracellular PPIA is a promising druggable target for ALS and support further studies to develop a therapy to arrest or slow the progression of the disease in patients.
Original languageItalian
Pages (from-to)1413-1427
Number of pages15
JournalJournal of Neuroscience
Volume37
Issue number6
DOIs
Publication statusPublished - Feb 8 2017

Cite this

Targeting extracellular cyclophilin a reduces neuroinflammation and extends survival in a mouse model of amyotrophic lateral sclerosis. / Pasetto, Laura; Pozzi, Silvia; Castelnovo, Mariachiara; Basso, Manuela; Estevez, Alvaro G.; Fumagalli, Stefano; De Simoni, Maria Grazia; Castellaneta, Valeria; Bigini, Paolo; Restelli, Elena; Chiesa, Roberto; Trojsi, Francesca; Monsurrò, Maria Rosaria; Callea, Leonardo; Malešević, Miroslav; Fischer, Gunter; Freschi, Mattia; Tortarolo, Massimo; Bendotti, Caterina; Bonetto, Valentina.

In: Journal of Neuroscience, Vol. 37, No. 6, 08.02.2017, p. 1413-1427.

Research output: Contribution to journalArticle

Pasetto, Laura ; Pozzi, Silvia ; Castelnovo, Mariachiara ; Basso, Manuela ; Estevez, Alvaro G. ; Fumagalli, Stefano ; De Simoni, Maria Grazia ; Castellaneta, Valeria ; Bigini, Paolo ; Restelli, Elena ; Chiesa, Roberto ; Trojsi, Francesca ; Monsurrò, Maria Rosaria ; Callea, Leonardo ; Malešević, Miroslav ; Fischer, Gunter ; Freschi, Mattia ; Tortarolo, Massimo ; Bendotti, Caterina ; Bonetto, Valentina. / Targeting extracellular cyclophilin a reduces neuroinflammation and extends survival in a mouse model of amyotrophic lateral sclerosis. In: Journal of Neuroscience. 2017 ; Vol. 37, No. 6. pp. 1413-1427.
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AU - Estevez, Alvaro G.

AU - Fumagalli, Stefano

AU - De Simoni, Maria Grazia

AU - Castellaneta, Valeria

AU - Bigini, Paolo

AU - Restelli, Elena

AU - Chiesa, Roberto

AU - Trojsi, Francesca

AU - Monsurrò, Maria Rosaria

AU - Callea, Leonardo

AU - Malešević, Miroslav

AU - Fischer, Gunter

AU - Freschi, Mattia

AU - Tortarolo, Massimo

AU - Bendotti, Caterina

AU - Bonetto, Valentina

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N2 - Neuroinflammationis amajor hallmarkof amyotrophiclateral sclerosis (ALS), whichis currentlyuntreatable. Several anti-inflammatory compounds have been evaluated in patients and in animal models of ALS, but have been proven disappointing in part because effective targets have not yet been identified. Cyclophilin A, also known as peptidylprolyl cis-/trans-isomerase A (PPIA), as a foldase is beneficial intracellularly, but extracellularly has detrimental functions. We found that extracellular PPIA is a mediator of neuroinflammation in ALS. It is a major inducer of matrix metalloproteinase 9 and is selectively toxic for motor neurons. High levels of PPIA were found in the CSF of SOD1G93A mice and rats and sporadic ALS patients, suggesting that our findings may be relevant for familial and sporadic cases. A specific inhibitor of extracellular PPIA, MM218, given at symptom onset, rescued motor neurons and extended survival in the SOD1G93A mouse model of familial ALS by 11 d. The treatment resulted in the polarization of glia toward a prohealing phenotype associated with reduced NF-κB activation, proinflammatory markers, endoplasmic reticulum stress, and insoluble phosphorylated TDP-43. Our results indicates that extracellular PPIA is a promising druggable target for ALS and support further studies to develop a therapy to arrest or slow the progression of the disease in patients.

AB - Neuroinflammationis amajor hallmarkof amyotrophiclateral sclerosis (ALS), whichis currentlyuntreatable. Several anti-inflammatory compounds have been evaluated in patients and in animal models of ALS, but have been proven disappointing in part because effective targets have not yet been identified. Cyclophilin A, also known as peptidylprolyl cis-/trans-isomerase A (PPIA), as a foldase is beneficial intracellularly, but extracellularly has detrimental functions. We found that extracellular PPIA is a mediator of neuroinflammation in ALS. It is a major inducer of matrix metalloproteinase 9 and is selectively toxic for motor neurons. High levels of PPIA were found in the CSF of SOD1G93A mice and rats and sporadic ALS patients, suggesting that our findings may be relevant for familial and sporadic cases. A specific inhibitor of extracellular PPIA, MM218, given at symptom onset, rescued motor neurons and extended survival in the SOD1G93A mouse model of familial ALS by 11 d. The treatment resulted in the polarization of glia toward a prohealing phenotype associated with reduced NF-κB activation, proinflammatory markers, endoplasmic reticulum stress, and insoluble phosphorylated TDP-43. Our results indicates that extracellular PPIA is a promising druggable target for ALS and support further studies to develop a therapy to arrest or slow the progression of the disease in patients.

KW - Amyotrophic lateral sclerosis

KW - Cyclophilin A

KW - Neuroinflammation

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