title: Targeting Extracellular Cyclophilin A Reduces Neuroinflammation and Extends Survival in a Mouse Model of Amyotrophic Lateral Sclerosis.
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.
authors.affiliation: Department of Molecular Biochemistry and Pharmacology.
authors.forename: Laura
authors.initials: L
authors.lastname: Pasetto
authors.affiliation: Department of Molecular Biochemistry and Pharmacology.
authors.forename: Silvia
authors.initials: S
authors.lastname: Pozzi
authors.affiliation: Department of Molecular Biochemistry and Pharmacology.
authors.forename: Mariachiara
authors.initials: M
authors.lastname: Castelnovo
authors.affiliation: Centre for Integrative Biology (CIBIO), University of Trento, 38123 Trento, Italy.
authors.forename: Manuela
authors.initials: M
authors.lastname: Basso
authors.affiliation: Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, Florida 32816.
authors.forename: Alvaro G
authors.initials: AG
authors.lastname: Estevez
authors.affiliation: Department of Neurosciences, and.
authors.forename: Stefano
authors.initials: S
authors.lastname: Fumagalli
authors.affiliation: Department of Neurosciences, and.
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: De Simoni
authors.affiliation: Department of Molecular Biochemistry and Pharmacology.
authors.forename: Valeria
authors.initials: V
authors.lastname: Castellaneta
authors.affiliation: Department of Molecular Biochemistry and Pharmacology.
authors.forename: Paolo
authors.identifier: 0000-0002-0239-9532
authors.initials: P
authors.lastname: Bigini
authors.affiliation: Department of Neurosciences, and.
authors.forename: Elena
authors.initials: E
authors.lastname: Restelli
authors.affiliation: Department of Neurosciences, and.
authors.forename: Roberto
authors.initials: R
authors.lastname: Chiesa
authors.affiliation: Department of Medical, Surgical, Neurological, Metabolic and Aging Sciences, Second University of Naples, 80131 Naples, Italy.
authors.forename: Francesca
authors.identifier: 0000-0002-3790-8018
authors.initials: F
authors.lastname: Trojsi
authors.affiliation: Department of Medical, Surgical, Neurological, Metabolic and Aging Sciences, Second University of Naples, 80131 Naples, Italy.
authors.forename: Maria Rosaria
authors.initials: MR
authors.lastname: Monsurrò
authors.affiliation: IRCCS Fondazione "Don Carlo Gnocchi", 20121 Milano, Italy.
authors.forename: Leonardo
authors.initials: L
authors.lastname: Callea
authors.affiliation: Institute of Biochemistry and Biotechnology, Martin Luther University Halle-Wittenberg, 06099 Halle, Germany, and.
authors.forename: Miroslav
authors.initials: M
authors.lastname: Malešević
authors.affiliation: Max-Planck-Institute for Biophysical Chemistry Göttingen, BO Halle, 06120 Halle, Germany.
authors.forename: Gunter
authors.initials: G
authors.lastname: Fischer
authors.affiliation: Italian Foundation for research on ALS (AriSLA) Animal Facility, IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, 20156 Milano, Italy.
authors.forename: Mattia
authors.identifier: 0000-0003-0800-5087
authors.initials: M
authors.lastname: Freschi
authors.affiliation: Department of Neurosciences, and.
authors.forename: Massimo
authors.initials: M
authors.lastname: Tortarolo
authors.affiliation: Department of Neurosciences, and.
authors.forename: Caterina
authors.initials: C
authors.lastname: Bendotti
authors.affiliation: Department of Molecular Biochemistry and Pharmacology, valentina.bonetto@marionegri.it.
authors.forename: Valentina
authors.identifier: 0000-0003-0456-2054
authors.initials: V
authors.lastname: Bonetto
mesh_terms: D000328:Adult; D000368:Aged; D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality; D000818:Animals; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D018920:Coculture Techniques; D021984:Cyclophilin A / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004195:Disease Models, Animal; D016503:Drug Delivery Systems / Q000379:methods; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D045604:Extracellular Fluid / Q000187:drug effects / Q000378:metabolism*; D005260:Female; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008875:Middle Aged; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D015996:Survival Rate / Q000639:trends
chemical_list: D004791:Enzyme Inhibitors; D018836:Inflammation Mediators; D021984:Cyclophilin A
keywords: amyotrophic lateral sclerosis; cyclophilin A; neuroinflammation