Neuroinflammation is a major hallmark of amyotrophic lateral sclerosis (ALS), which is currently untreatable. Several anti-inflammatory compounds have been evaluated in patients and animal models of ALS, but have been proved disappointing, in part because effective targets have not yet been identified. Cyclophilin 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 cerebrospinal fluid of SOD1(G93A) 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 SOD1(G93A) mouse model of familial ALS by 11 days. The treatment resulted in the polarization of glia toward a pro-healing phenotype associated with reduced NF-κB activation, pro-inflammatory 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.

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

TROJSI, Francesca;MONSURRO', Maria Rosaria;
2016

Abstract

Neuroinflammation is a major hallmark of amyotrophic lateral sclerosis (ALS), which is currently untreatable. Several anti-inflammatory compounds have been evaluated in patients and animal models of ALS, but have been proved disappointing, in part because effective targets have not yet been identified. Cyclophilin 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 cerebrospinal fluid of SOD1(G93A) 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 SOD1(G93A) mouse model of familial ALS by 11 days. The treatment resulted in the polarization of glia toward a pro-healing phenotype associated with reduced NF-κB activation, pro-inflammatory 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.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11591/367735
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