Translocator Protein Ligand Protects Against Neurodegeneration in the MPTP Mouse Model of Parkinsonism
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This Accepted Manuscript has not been copyedited and formatted. The final version may differ from this version. Research Articles: Neurobiology of Disease Translocator protein ligand protects against neurodegeneration in the MPTP mouse model of Parkinsonism Jing Gong1, Éva M. Szegő1, Andrei Leonov4, Eva Benito5, Stefan Becker4, Andre Fischer5,6, Markus Zweckstetter3,4,5, Tiago Outeiro2,3,7 and Anja Schneider1,8 1German Center for Neurodegenerative Diseases, DZNE, Sigmund-Freud-Str. 27, 53127 Bonn, Germany 2Department of Experimental Neurodegeneration, Center for Biostructural Imaging of Neurodegeneration, University Medical Center Göttingen, University of Göttingen, Waldweg 33, 37075 Göttingen, Germany 3Cluster of Excellence, Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB), Humboldtallee 23, 30703 Göttingen, Germany 4Max-Planck-Institute for Biophysical Chemistry, Am Faßberg 11, 37077, Göttingen, Germany 5German Center for Neurodegenerative Diseases, DZNE, Von-Siebold-Str. 3a, 37075 Göttingen, Germany 6Department of Psychiatry and Psychotherapy, University Medical Center, Von-Siebold-Str. 3b, 37075 Göttingen, Germany 7Institute of Neuroscience, The Medical School, Newcastle University, Framlington Place, Newcastle Upon Tyne, NE2 4HH, UK 8Department of Neurodegenerative Diseases and Geriatric Psychiatry, University Hospital Bonn, Sigmund- Freud-Str.25, 53127 Bonn, Germany https://doi.org/10.1523/JNEUROSCI.2070-18.2019 Received: 14 August 2018 Revised: 11 January 2019 Accepted: 15 January 2019 Published: 22 February 2019 Author contributions: J.G., E.S., E.B., A.F., M.Z., T.F.O., and A.S. designed research; J.G., E.S., and E.B. performed research; J.G., E.S., E.B., A.F., and A.S. analyzed data; A.L., S.B., and M.Z. contributed unpublished reagents/analytic tools; A.S. wrote the paper. Conflict of Interest: The authors declare no competing financial interests. JG was supported by a scholarship from China Scholarship Council. EMSZ was supported by the Dorothea Schlözer fellowship. AF was supported by core funds from the DZNE, the DFG projects FI981/9-1 and SPP1738 (FI981-11-1) and the EU (ERC consolidator grant DEPICODE). MZ was supported by the DFG Collaborative Research Center 803 (project A11). TFO was supported by the DFG Center for Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB) and by SFB1286 (project B6). AS was supported by the DFG Center for Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB), DZNE core funds, the DFG project SCHN1265/1-1, and Michael J Fox Foundation (MJFF) grant. Correspondence should be addressed to To whom correspondence should be addressed. Phone: + +49-228-43302450, Email: [email protected] Cite as: J. Neurosci 2019; 10.1523/JNEUROSCI.2070-18.2019 Alerts: Sign up at www.jneurosci.org/alerts to receive customized email alerts when the fully formatted version of this article is published. Accepted manuscripts are peer-reviewed but have not been through the copyediting, formatting, or proofreading process. Copyright © 2019 the authors 1 Translocator protein ligand protects against neurodegeneration in the MPTP mouse 2 model of Parkinsonism 3 Jing Gong1#, Éva M. Szegő2,3#, Andrei Leonov4, Eva Benito5, Stefan Becker4, Andre 4 Fischer5,6, Markus Zweckstetter3,4,5, Tiago Outeiro2,3,7, Anja Schneider1,8* 5 1German Center for Neurodegenerative Diseases, DZNE, Sigmund-Freud-Str. 27, 53127 6 Bonn, Germany 7 2Department of Experimental Neurodegeneration, Center for Biostructural Imaging of 8 Neurodegeneration, University Medical Center Göttingen, University of Göttingen, Waldweg 9 33, 37075 Göttingen, Germany 10 3Cluster of Excellence, Nanoscale Microscopy and Molecular Physiology of the Brain 11 (CNMPB), Humboldtallee 23, 30703 Göttingen, Germany 12 4 Max-Planck-Institute for Biophysical Chemistry, Am Faßberg 11, 37077, Göttingen, 13 Germany 14 5 German Center for Neurodegenerative Diseases, DZNE, Von-Siebold-Str. 3a, 37075 15 Göttingen, Germany 16 6 Department of Psychiatry and Psychotherapy, University Medical Center, Von-Siebold-Str. 17 3b, 37075 Göttingen, Germany 18 7 Institute of Neuroscience, The Medical School, Newcastle University, Framlington Place, 19 Newcastle Upon Tyne, NE2 4HH, UK 20 8Department of Neurodegenerative Diseases and Geriatric Psychiatry, University Hospital 21 Bonn, Sigmund-Freud-Str.25, 53127 Bonn, Germany 22 #contributed equally 1 23 * to whom correspondence should be addressed. Phone: ++49-228-43302450, Email: 24 [email protected] 25 26 Abbreviated title: TSPO ligand protects against neurodegeneration 27 28 Number of pages: 45, number of figures: 11, number of tables: 1, number of words for 29 Abstract 165, Introduction 817, Discussion 1379. 30 31 Conflict of Interest 32 The authors declare no competing financial interests. 33 34 Acknowledgements 35 JG was supported by a scholarship from China Scholarship Council. EMSZ was supported by 36 the Dorothea Schlözer fellowship. AF was supported by core funds from the DZNE, the DFG 37 projects FI981/9-1 and SPP1738 (FI981-11-1) and the EU (ERC consolidator grant 38 DEPICODE). MZ was supported by the DFG Collaborative Research Center 803 (project 39 A11). TFO was supported by the DFG Center for Nanoscale Microscopy and Molecular 40 Physiology of the Brain (CNMPB) and by SFB1286 (project B6). AS was supported by the 41 DFG Center for Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB), 42 DZNE core funds, the DFG project SCHN1265/1-1, and Michael J Fox Foundation (MJFF) 43 grant. 44 45 2 46 Abstract 47 Parkinson’s disease (PD) is the second most common neurodegenerative disease, after 48 Alzheimer’s disease. PD is a movement disorder with characteristic motor features that arise 49 due to the loss of dopaminergic neurons from the substantia nigra. Although symptomatic 50 treatment by the dopamine precursor levodopa and dopamine agonists can improve motor 51 symptoms, no disease-modifying therapy exists yet. Here, we show that Emapunil (AC-5216, 52 XBD-173), a synthetic ligand of the translocator protein 18 (TSPO), ameliorates degeneration 53 of dopaminergic neurons, preserves striatal dopamine metabolism and prevents motor 54 dysfunction in female mice treated with the 1-methyl-4-phenyl-1,-2,-3,-6-tetrahydropyridine 55 (MPTP), as a model of parkinsonism. We found that Emapunil modulates the inositol 56 requiring kinase 1 α (IRE α)/-X-box binding protein 1 (XBP1) unfolded protein response 57 pathway and induces a shift from pro- towards anti-inflammatory microglia activation. 58 Previously, Emapunil was shown to cross the blood brain barrier and to be safe and well- 59 tolerated in a phase II clinical trial. Therefore, our data suggest that Emapunil may be a 60 promising approach in the treatment of Parkinson’s disease. 61 62 Keywords: TSPO, Parkinson’s disease, neurodegeneration, microglia 63 64 Significance statement 65 Our study reveals a beneficial effect of Emapunil on dopaminergic neuron survival, dopamine 66 metabolism and motor phenotype in the MPTP mouse model of parkinsonism. In addition, 67 our work uncovers molecular networks which mediate neuroprotective effects of Emapunil, 68 including microglial activation state and unfolded protein response pathways. These findings 69 not only contribute to our understanding of biological mechanisms of TSPO function but also 70 indicate that TSPO may be a promising therapeutic target. We thus propose to further validate 3 71 Emapunil in other Parkinson’s disease mouse models and subsequently in clinical trials to 72 treat Parkinson’s disease. 73 74 Introduction 75 Parkinson’s disease is a devastating age-associated movement disorder with high prevalence 76 in the elderly population. Motor symptoms arise due to the progressive loss of dopaminergic 77 neurons from the substantia nigra pars compacta (SNpc), but the precise cause is still unclear. 78 Surviving neurons display intracellular inclusions of D-synuclein, known as Lewy bodies 79 (Spillantini et al., 1998). In Parkinson’s disease patients and animal models, 80 neurodegeneration is accompanied by neuroinflammation (McGeer et al., 1988; Imamura et 81 al., 2003; Miklossy et al., 2006; Brochard et al., 2009; Hirsch and Hunot, 2009; Harms et al., 82 2017), potentially triggered by the release of ATP (Davalos et al., 2005), neuromelanin 83 (Wilms et al., 2003; Zhang et al., 2013) or aggregated D-synuclein (Zhang et al., 2005b; 84 Couch et al., 2011; Acosta et al., 2015) from decaying neurons. These pro-inflammatory 85 stimuli may activate microglia to secrete cytokines and free radicals which further contribute 86 to oxidative stress, neurotoxicity and disease progression (Block et al., 2007) (Hirsch and 87 Hunot, 2009). In Parkinson’s disease patients, higher levels of cytokines were detected in 88 cerebrospinal fluid (Tufekci et al., 2011), serum (Eidson et al., 2017), substantia nigra and 89 striatum (Knott et al., 2000; Teismann et al., 2003; Mogi et al., 2007) as compared to controls. 90 Several genes associated with familial forms of Parkinson’s disease, including SNCA, LRKK2, 91 PARK2, PINK2 and DJ-1, have been linked with immune response (Waak et al., 2009; Gardet 92 et al., 2010; Gu et al., 2010; Akundi et al., 2011; Gillardon et al., 2012; Moehle et al., 2012) 93 and polymorphisms in genes encoding inflammatory cytokines are associated with a higher 94 risk for sporadic Parkinson’s disease (Wahner et al., 2007; Deleidi and Gasser, 2013). 95 Conversely, Minocyclin, an inhibitor of microglial activation, can protect against 4 96 dopaminergic neuron