Abstract
| Original language | Italian |
|---|---|
| Pages (from-to) | 1413-1427 |
| Number of pages | 15 |
| Journal | Journal of Neuroscience |
| Volume | 37 |
| Issue number | 6 |
| DOIs | |
| Publication status | Published - 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 journal › Article
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TY - JOUR
T1 - Targeting extracellular cyclophilin a reduces neuroinflammation and extends survival in a mouse model of amyotrophic lateral sclerosis
AU - Pasetto, Laura
AU - Pozzi, Silvia
AU - Castelnovo, Mariachiara
AU - Basso, Manuela
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
PY - 2017/2/8
Y1 - 2017/2/8
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
U2 - 10.1523/JNEUROSCI.2462-16.2016
DO - 10.1523/JNEUROSCI.2462-16.2016
M3 - Articolo
VL - 37
SP - 1413
EP - 1427
JO - Journal of Neuroscience
JF - Journal of Neuroscience
SN - 0270-6474
IS - 6
ER -