1. Targeting extracellular cyclophilin A reduces neuroinflammation and extends survival in a mouse model of amyotrophic lateral sclerosis
- Author
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Maria Rosaria Monsurrò, Maria Grazia De Simoni, Stefano Fumagalli, Massimo Tortarolo, Francesca Trojsi, Alvaro G. Estévez, Gunter Fischer, Valentina Bonetto, Mariachiara Castelnovo, Caterina Bendotti, Paolo Bigini, Miroslav Malesevic, Silvia Pozzi, Leonardo Callea, Roberto Chiesa, Mattia Freschi, Laura Pasetto, Elena Restelli, Valeria Castellaneta, Manuela Basso, 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, Monsurro', Maria Rosaria, Callea, Leonardo, Malešević, Miroslav, Fischer, Gunter, Freschi, Mattia, Tortarolo, Massimo, Bendotti, Caterina, and Bonetto, Valentina
- Subjects
0301 basic medicine ,Male ,129 Strain ,Inbred C57BL ,Transgenic ,Mice ,0302 clinical medicine ,Drug Delivery Systems ,Neuroinflammation ,Amyotrophic lateral sclerosis ,Enzyme Inhibitors ,Research Articles ,Cells, Cultured ,Neurons ,Cultured ,General Neuroscience ,Middle Aged ,Phenotype ,Survival Rate ,Female ,Inflammation Mediators ,Cyclophilin A ,Adult ,Aged ,Amyotrophic Lateral Sclerosis ,Animals ,Cell Survival ,Coculture Techniques ,Extracellular Fluid ,Humans ,Inflammation ,Mice, 129 Strain ,Mice, Inbred C57BL ,Mice, Transgenic ,Disease Models, Animal ,Neuroscience (all) ,Cells ,Biology ,Proinflammatory cytokine ,03 medical and health sciences ,Mediator ,Extracellular ,medicine ,Animal ,Endoplasmic reticulum ,medicine.disease ,030104 developmental biology ,Disease Models ,Immunology ,Cancer research ,030217 neurology & neurosurgery - 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 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 SOD1G93Amice 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 SOD1G93Amouse 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.SIGNIFICANCE STATEMENTWe provide evidence that extracellular cyclophilin A, also known as peptidylprolyl cis-/trans-isomerase A (PPIA), is a mediator of the neuroinflammatory reaction in amyotrophic lateral sclerosis (ALS) and is toxic for motor neurons. Supporting this, a specific extracellular PPIA inhibitor reduced neuroinflammation, rescued motor neurons, and extended survival in the SOD1G93Amouse model of familial ALS. Our findings suggest selective pharmacological inhibition of extracellular PPIA as a novel therapeutic strategy, not only for SOD1-linked ALS, but possibly also for sporadic ALS. This approach aims to address the neuroinflammatory reaction that is a major hallmark of ALS. However, given the complexity of the disease, a combination of therapeutic approaches may be necessary.
- Published
- 2016