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Targeting Extracellular Cyclophilin a Reduces Neuroinflammation and Extends Survival in a Mouse Model of Amyotrophic Lateral Sclerosis

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Targeting Extracellular Cyclophilin a Reduces Neuroinflammation and Extends Survival in a Mouse Model of Amyotrophic Lateral Sclerosis The Journal of Neuroscience, February 8, 2017 • 37(6):1413–1427 • 1413 Neurobiology of Disease Targeting Extracellular Cyclophilin A Reduces Neuroinflammation and Extends Survival in a Mouse Model of Amyotrophic Lateral Sclerosis Laura Pasetto,1* Silvia Pozzi,1* Mariachiara Castelnovo,1 Manuela Basso,4 Alvaro G. Estevez,5 Stefano Fumagalli,2 Maria Grazia De Simoni,2 Valeria Castellaneta,1 XPaolo Bigini,1 Elena Restelli,2 Roberto Chiesa,2 XFrancesca Trojsi,6 Maria Rosaria Monsurro`,6 Leonardo Callea,7 Miroslav Malesˇevic´,8 Gunter Fischer,9 XMattia Freschi,3 Massimo Tortarolo,2 Caterina Bendotti,2 and XValentina Bonetto1 1Department of Molecular Biochemistry and Pharmacology, 2Department of Neurosciences, and 3Italian Foundation for research on ALS (AriSLA) Animal Facility, IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, 20156 Milano, Italy, 4Centre for Integrative Biology (CIBIO), University of Trento, 38123 Trento, Italy, 5Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, Florida 32816, 6Department of Medical, Surgical, Neurological, Metabolic and Aging Sciences, Second University of Naples, 80131 Naples, Italy, 7IRCCS Fondazione “Don Carlo Gnocchi”, 20121 Milano, Italy, 8Institute of Biochemistry and Biotechnology, Martin Luther University Halle-Wittenberg, 06099 Halle, Germany, and 9Max-Planck-Institute for Biophysical Chemistry Go¨ttingen, BO Halle, 06120 Halle, Germany Neuroinflammationisamajorhallmarkofamyotrophiclateralsclerosis(ALS),whichiscurrentlyuntreatable.Severalanti-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-␬B 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. Key words: amyotrophic lateral sclerosis; cyclophilin A; neuroinflammation Significance Statement We 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 extracel- lular PPIA inhibitor reduced neuroinflammation, rescued motor neurons, and extended survival in the SOD1G93A mouse 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. Introduction genetically dominant disorder in which mutations in Cu/Zn su- Amyotrophic lateral sclerosis (ALS) is a devastating, incurable peroxide dismutase (SOD1) and C9ORF72 genes are the most neurodegenerative disease that primarily affects motor neurons common cause. Independently from the etiology, it is now estab- in the brain and spinal cord. Most cases are sporadic, with un- lished that ALS is a multifactorial disease involving different known etiology. Approximately 10% have a family history of a pathogenic mechanisms that require multiple non-neuronal cells Received Aug. 3, 2016; revised Oct. 24, 2016; accepted Nov. 15, 2016. This work was supported by Telethon Italy (Grant TCR08002 to V.B.), Italian Foundation for research on ALS Author contributions: L.P., S.P., A.G.E., M.G.D.S., P.B., R.C., M.R.M., G.F., C.B., and V.B. designed research; L.P., (AriSLA) (Grant CypALS to V.B.), and the European Community’s Health Seventh Framework Programme (FP7/ S.P., M.C., M.B., S.F., V.C., E.R., F.T., L.C., M.M., M.F., and M.T. performed research; L.P., S.P., M.B., S.F., P.B., M.F., 2007–2013 under Grant 259867 to C.B). We thank Dr. Marco Marzo for contribution to the in vitro experiments, Dr. C.B., and V.B. analyzed data; L.P., S.P., M.B., A.G.E., C.B., and V.B. wrote the paper. Giorgia Spano for help in collecting animal tissues, and Judith Baggott for editorial assistance. 1414 • J. Neurosci., February 8, 2017 • 37(6):1413–1427 Pasetto, Pozzi et al. • Extracellular Cyclophilin A in ALS for rapid disease progression and motor neuron death (Rob- models of chronic and acute inflammatory conditions by in- berecht and Philips, 2013). In particular, astrocytes and micro- hibiting its PPIase activity (Hoffmann and Schiene-Fischer, glia, in association with the neurodegenerative process, acquire a 2014). neuroinflammatory phenotype and elicit neuroinflammatory We identified PPIA as an hallmark of disease in peripheral blood processes that contribute actively to motor neuron degeneration mononuclear cells and spinal cord of sporadic ALS patients and through a non-cell-autonomous mechanism (Boille´e et al., 2006; mutant SOD1 animal models (Massignan et al., 2007; Basso et al., Yamanaka et al., 2008). 2009; Nardo et al., 2011). Here, we report that, under ALS condi- Several compounds with anti-inflammatory properties have tions, high levels of extracellular PPIA exert a toxic effect specifically been evaluated in the mutant SOD1 mouse model of familial toward motor neurons through an EMMPRIN-dependent pathway. ALS. Many of those that had a positive effect on astrocytosis and We have therefore developed a therapeutic strategy that, by inhibit- microgliosis delayed the disease onset, but had only a mild or no ing exclusively PPIA extracellularly, protects motor neurons and re- effect on its progression (Drachman et al., 2002; Kriz et al., 2002; duces the neuroinflammatory response. Van Den Bosch et al., 2002; Schu¨tz et al., 2005; Kiaei et al., 2006; Neymotin et al., 2009). More promising results have been ob- tained in SOD1G93A mice by transgenic inhibition of microglial Materials and Methods NF-kB (Frakes et al., 2014), the master regulator of the inflam- Antibodies. Antibodies for immunoblot (Western/dot blot) (IB), immu- matory response, and by knocking out matrix metalloproteinase nohistochemistry (IH), and immunocytochemistry (IC) were as follows: ␬ rabbit polyclonal anti-choline acetyltransferase (ChAT) antibody (1: 9 (MMP-9) (Kaplan et al., 2014), a NF- B transcriptionally acti- 1000 for IH; Immunological Science); mouse monoclonal anti-glial vated gene that contributes to the neuroinflammatory response fibrillary acidic protein (GFAP) antibody (1:1000 for IH; Millipore, in many neurological diseases (Yong et al., 2001). RRID:AB_94844); rat polyclonal anti-CD11b antibody (1:800 for IH; Cyclophilin A, also known as peptidylprolyl cis-/trans- Millipore); rat monoclonal anti-CD68 (1:200 for IH; Serotec, RRID: isomerase A (PPIA), is an enzyme acting as an acceleration factor AB_322219); mouse monoclonal anti-lamin A/C antibody (1:500 for IB; in protein folding and assembly and is the main target of the Millipore, RRID:AB_94752); mouse monoclonal anti-glyceraldehyde immunosuppressive drug cyclosporine A (CsA) (Fischer et al., 3-phosphate dehydrogenase (GAPDH) antibody (1:10000 for IB; Milli- 1984; Handschumacher et al., 1984). It is expressed ubiquitously pore, RRID:AB_10615768); rabbit polyclonal anti-mitochondrial im- and abundantly, with the highest expression in the CNS (Go¨ldner port receptor subunit TOM20 (1:1000 for IB; Santa Cruz Biotechnology, and Patrick, 1996). It is mainly cytoplasmic, but is also secreted RRID:AB_2207533); mouse monoclonal anti-cytochrome C (1:500 for IB; BD Biosciences, RRID:AB_396417); rabbit polyclonal anti-PPIA an- extracellularly by different cell types, including neurons (Faure´et tibody (1:2500 for IB; 1:1000 for IH; Millipore, RRID:AB_2252847); al., 2006). Its secretion in several cases is constitutive and in- mouse monoclonal anti-SMI32 antibody (1:2500 for IC; Covance, RRID: creases under stress and/or pathological conditions (Hoffmann AB_509997); mouse monoclonal anti-NeuN antibody (1:250 for IC; Mil- and Schiene-Fischer, 2014). Intracellular PPIA is beneficial: it lipore, RRID:AB_2298772); goat polyclonal anti-mouse EMMPRIN protects cells from oxidative stress in various ways (Ja¨schke et al., antibody (1:1000 for IB; 1:500 for IC; Santa Cruz Biotechnology, RRID: 1998; Lee et al., 2001) and mitigates toxicity induced by mutant AB_2066959); rabbit polyclonal anti-apoptosis-inducing factor (AIF) SOD1 protein aggregates (Lee et al., 1999). We reported recently antibody (1:1000 IB; Cell Signaling Technology, RRID:AB_2224542); that PPIA regulates key TAR DNA-binding protein 43 (TDP-43) rabbit polyclonal anti-tumor necrosis factor ␣ (TNF␣)
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