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Α-Synuclein Oligomers Induce Glutamate Release from Astrocytes

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Α-Synuclein Oligomers Induce Glutamate Release from Astrocytes Research Articles: Neurobiology of Disease α-Synuclein Oligomers Induce Glutamate Release from Astrocytes and Excessive Extrasynaptic NMDAR Activity in Neurons, Thus Contributing to Synapse Loss https://doi.org/10.1523/JNEUROSCI.1871-20.2020 Cite as: J. Neurosci 2021; 10.1523/JNEUROSCI.1871-20.2020 Received: 16 July 2020 Revised: 22 December 2020 Accepted: 28 December 2020 This Early Release article has been peer-reviewed and accepted, but has not been through the composition and copyediting processes. The final version may differ slightly in style or formatting and will contain links to any extended data. Alerts: Sign up at www.jneurosci.org/alerts to receive customized email alerts when the fully formatted version of this article is published. Copyright © 2021 the authors 1 Neurobiology of Disease 2 3 α-Synuclein Oligomers Induce Glutamate Release from Astrocytes and Excessive 4 Extrasynaptic NMDAR Activity in Neurons, Thus Contributing to Synapse Loss 5 6 Dorit Trudler,1 Sara Sanz-Blasco,3 Yvonne S. Eisele,4 Swagata Ghatak,1 Karthik Bodhinathan,3 7 Mohd Waseem Akhtar,3 William P. Lynch,4 Juan C. Piña-Crespo,1,3 Maria Talantova,1,2 Jeffery 8 W. Kelly, 5 and Stuart A. Lipton1,2,6 9 10 1Neuroscience Translational Center and Department of Molecular Medicine, The Scripps 11 Research Institute, La Jolla, California 92037, USA. 12 2Neurodegenerative Disease Center, Scintillon Institute, San Diego, California 92121, USA. 13 3Center for Neuroscience and Aging Research, Sanford Burnham Prebys Medical Discovery 14 Institute, La Jolla, CA 92037, 15 4Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, 16 OH 44272 and Brain Health Research Institute, Kent State University, Kent, OH 44242 17 5Department of Chemistry, The Scripps Research Institute, La Jolla, California 92037, 18 6Department of Neurosciences, University of California, San Diego, School of Medicine, La 19 Jolla, California 92093 20 21 Correspondence regarding the manuscript should be addressed to S.A.L. ([email protected]). 22 23 ⁘ Number of pages: currently 37 24 ⁘ Number of figures: 8 25 ⁘ Number of words: Abstract: 206; Significance statement: 115; Introduction: 661; Discussion: 882 1 26 ⁘ Conflict of Interest statement 27 The authors declare that S.A.L. is an inventor on worldwide patents for the use of memantine 28 and NitroSynapsin for neurodegenerative and neurodevelopmental disorders. Per Harvard 29 University guidelines, S.A.L. participates in a royalty-sharing agreement with his former 30 institution Boston Children’s Hospital/Harvard Medical School, which licensed the drug 31 memantine (Namenda®) to Forest Laboratories, Inc./Actavis/Allergan, Inc. NitroSynapsin is 32 licensed to EuMentis Therapeutics, Inc. K.B. is currently (but not during the time of the study) 33 an employee of and holds stock/stock options in Biogen, Inc., which is involved in the research, 34 development and commercialization of therapies for neurological disorders. The other authors 35 declare no financial conflicts of interest relevant to this publication. 36 37 ACKNOWLEDGMENTS 38 The authors wish to thank Loren L. Looger and Jonathan S. Marvin for kindly providing the 39 iGluSnFR probe, and Michael S. Sailor (UCSD) for the use of his dynamic light scattering 40 (DLS) instrument. Figure 8 was created with BioRender.com. This work was supported in part 41 by NIH grants DP1 DA041722, R01 DA048882, R01 NS086890, R01 AG056259, and RF1 42 AG057409 (to S.A.L.). Y.S.E. was supported by an NIH K99/R00 Pathway to Independence 43 Award from the NIA (K99/R00AG050764). 44 Current affiliation: Y.S. E., Department of Medicine, Division of Cardiology, University of 45 Pittsburgh, Pittsburgh, Pennsylvania 15219. K.B., Biogen, 225 Binney St., Cambridge, MA 46 02142. 47 48 AUTHOR CONTRIBUTIONS 49 D.T., M.T and S.A.L. designed and carried out the majority of the experiments and performed 50 data analysis. S.S.B performed FRET experiments. Y.S.E. performed AFM analysis. S.W. and 2 51 M.W.A assisted with organotypic slice preparation. K.B. and M.T performed electrophysiology 52 experiments. J.C.P-C performed microdialysis experiments. W.P.L and J.W.K assisted in critical 53 thinking and discussion. D.T, M.T and S.A.L analyzed data and wrote the manuscript with input 54 from all of the co-authors. 3 55 Abstract 56 Synaptic and neuronal loss are major neuropathological characteristics of Parkinson’s disease 57 (PD). Misfolded protein aggregates in the form of Lewy bodies, comprised mainly of α- 58 synuclein (αSyn), are associated with disease progression, and have also been linked to other 59 neurodegenerative diseases, including Lewy body dementia (LBD), Alzheimer’s disease (AD, 60 and Frontotemporal dementia (FTD). However, the effects of αSyn and its mechanism of 61 synaptic damage remain incompletely understood. Here, we show that αSyn oligomers induce 62 Ca2+-dependent release of glutamate from astrocytes obtained from male and female mice, and 63 that mice overexpressing αSyn manifest increased tonic release of glutamate in vivo. In turn, this 64 extracellular glutamate activates glutamate receptors, including extrasynaptic NMDA receptors 65 (eNMDARs), on neurons both in culture and in hippocampal slices of αSyn-overexpressing 66 mice. Additionally, in patch-clamp recording from outside-out patches, we found that 67 oligomerized αSyn can directly activate eNMDARs. In organotypic slices, oligomeric αSyn 68 induces eNMDAR-mediated synaptic loss, which can be reversed by the drug NitroSynapsin. 69 When we expose human induced pluripotent stem cell (hiPSC)-derived cerebrocortical neurons 70 to αSyn, we find similar effects. Importantly, the improved NMDAR antagonist NitroSynapsin, 71 which selectively inhibits extrasynaptic over physiological synaptic NMDAR activity, protects 72 synapses from oligomeric αSyn-induced damage in our model systems, thus meriting further 73 study for its therapeutic potential. 74 4 75 Significance statement 76 Loss of synaptic function and ensuing neuronal loss is associated with disease progression in 77 Parkinson’s disease (PD), Lewy body dementia (LBD), and other neurodegenerative diseases. 78 However, the mechanism of synaptic damage remains incompletely understood. α-Synuclein 79 (αSyn) misfolds in PD/LBD, forming Lewy bodies and contributing to disease pathogenesis. 80 Here, we found misfolded/oligomeric αSyn releases excessive astrocytic glutamate, in turn 81 activating neuronal extrasynaptic NMDA receptors (eNMDARs), thereby contributing to 82 synaptic damage. Additionally, αSyn oligomers directly activate eNMDARs, further contributing 83 to damage. While the FDA-approved drug memantine has been reported to offer some benefit in 84 PD/LBD (Hershey and Coleman-Jackson, 2019), we find the improved eNMDAR antagonist 85 NitroSynapsin ameliorates αSyn-induced synaptic spine loss, providing potential disease- 86 modifying intervention in PD/LBD. 5 87 Introduction 88 Intracellular protein aggregates composed of α-synuclein (αSyn, encoded by the SNCA gene) 89 accumulate as Lewy bodies and Lewy neurites in neurons in several neurodegenerative 90 disorders, particularly in Parkinson’s disease (PD) and Lewy body dementia (LBD), but also in 91 frontotemporal dementia (FTD) and Alzheimer’s disease (AD) (Spillantini et al., 1997; Goedert, 92 2001; Irwin and Hurtig, 2018; Bassil et al., 2020). PD/LBD and other synucleinopathies are 93 associated with synaptic damage and neuronal loss that affects not only dopaminergic neurons in 94 the substantia nigra but also cerebrocortical and other neuronal subtypes. Yet Lewy body 95 pathology in not well correlated with cell death or clinical symptoms (Schulz-Schaeffer, 2010). 96 Evidence suggests αSyn aggregate-related synaptic dysfunction or dendritic synapse loss 97 contributes to PD/LBD pathogenesis (Schulz-Schaeffer, 2010). However, the precise mechanism 98 by which αSyn oligomers/aggregates cause synaptic loss and subsequent neuronal cell death is 99 not yet clear. 100 Soluble αSyn aggregates have been shown to exert pleiotropic pathological effects on 101 multiple cell types, including neurons, astrocytes and microglia, and on their organelles, such as 102 mitochondria (Guardia-Laguarta et al., 2014; Delenclos et al., 2019; Sulzer and Edwards, 2019; 103 Bras et al., 2020). Larger aggregates and pre-formed fibrils of αSyn have been shown to result in 104 decreased expression of synaptic proteins and eventually neuronal cell death (Volpicelli-Daley et 105 al., 2011). Other groups have shown that αSyn fibrils propagate and result in neurotoxicity; 106 moreover, different fibril strains have been associated with cell-type and brain region-specific 107 damage (Peelaerts et al., 2015; Lau et al., 2020). One reported effect on neurons of αSyn 108 oligomers, but not monomers or fibrils, involves increased NMDA receptor (NMDAR) and 109 calcium-permeable AMPA receptor (AMPAR) activation (Diogenes et al., 2012). Additionally, 6 110 large αSyn oligomers alter both pre- and postsynaptic mechanisms of AMPAR-mediated 111 synaptic transmission. This increased excitation, mediated by both NMDARs and AMPARs, 112 may contribute to neuronal cell death in synucleinopathies, by altering intracellular calcium 113 homeostasis (Huls et al., 2011). However, whether αSyn oligomers/fibrils interact with glutamate 114 receptors directly, indirectly, or both remains unclear. 115 Previously, we and others have shown that another misfolded protein, amyloid-β (Aβ) 116 oligomers, induce an increase in astrocytic Ca2+ levels with
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