Abstract
Cognitive decline and dementia in neurodegenerative diseases are associated with synapse dysfunction and loss, which may precede neuron loss by several years. While misfolded and aggregated α-synuclein is recognized in the disease progression of synucleinopathies, the nature of glutamatergic synapse dysfunction and loss remains incompletely understood. Using fluorescence-activated synaptosome sorting (FASS), we enriched excitatory glutamatergic synaptosomes from mice overexpressing human alpha-synuclein (h-αS) and wild-type littermates to unprecedented purity. Subsequent label-free proteomic quantification revealed a set of proteins differentially expressed upon human alpha-synuclein overexpression. These include overrepresented proteins involved in the synaptic vesicle cycle, ER–Golgi trafficking, metabolism and cytoskeleton. Unexpectedly, we found and validated a steep reduction of eukaryotic translation elongation factor 1 alpha (eEF1A1) levels in excitatory synapses at early stages of h-αS mouse model pathology. While eEF1A1 reduction correlated with the loss of postsynapses, its immunoreactivity was found on both sides of excitatory synapses. Moreover, we observed a reduction in eEF1A1 immunoreactivity in the cingulate gyrus neuropil of patients with Lewy body disease along with a reduction in PSD95 levels. Altogether, our results suggest a link between structural impairments underlying cognitive decline in neurodegenerative disorders and local synaptic defects. eEF1A1 may therefore represent a limiting factor to synapse maintenance.
Similar content being viewed by others
References
Abbas W, Kumar A, Herbein G (2015) The eEF1A proteins: at the crossroads of oncogenesis, apoptosis, and viral infections. Front Oncol 5:75. https://doi.org/10.3389/fonc.2015.00075
Amschl D, Neddens J, Havas D, Flunkert S, Rabl R, Römer H, Rockenstein E, Masliah E, Windisch M, Hutter-Paier B (2013) Time course and progression of wild type α-Synuclein accumulation in a transgenic mouse model. BMC Neurosci 14:1
Beckelman BC, Day S, Zhou X, Donohue M, Gouras GK, Klann E, Keene CD, Ma T (2016) Dysregulation of elongation factor 1A expression is correlated with synaptic plasticity impairments in Alzheimer’s disease. J Alzheimers Dis JAD 54:669–678. https://doi.org/10.3233/JAD-160036
Bellucci A, Zaltieri M, Navarria L, Grigoletto J, Missale C, Spano P (2012) From α-synuclein to synaptic dysfunctions: new insights into the pathophysiology of Parkinson’s disease. Brain Res 1476:183–202. https://doi.org/10.1016/j.brainres.2012.04.014
Ben Gedalya T, Loeb V, Israeli E, Altschuler Y, Selkoe DJ, Sharon R (2009) α-Synuclein and polyunsaturated fatty acids promote clathrin-mediated endocytosis and synaptic vesicle recycling. Traffic 10:218–234. https://doi.org/10.1111/j.1600-0854.2008.00853.x
Bendor JT, Logan TP, Edwards RH (2013) The function of α-synuclein. Neuron 79:1044–1066. https://doi.org/10.1016/j.neuron.2013.09.004
Biesemann C, Grønborg M, Luquet E, Wichert SP, Bernard V, Bungers SR, Cooper B, Varoqueaux F, Li L, Byrne JA, Urlaub H, Jahn O, Brose N, Herzog E (2014) Proteomic screening of glutamatergic mouse brain synaptosomes isolated by fluorescence activated sorting. EMBO J 33:157–170. https://doi.org/10.1002/embj.201386120
Blumenstock S, Rodrigues EF, Peters F, Blazquez-Llorca L, Schmidt F, Giese A, Herms J (2017) Seeding and transgenic overexpression of alpha-synuclein triggers dendritic spine pathology in the neocortex. EMBO Mol Med 9:716–731. https://doi.org/10.15252/emmm.201607305
Braak H, Del Tredici K, Rüb U, de Vos RA, Steur ENJ, Braak E (2003) Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol Aging 24:197–211
Bunai F, Ando K, Ueno H, Numata O (2006) Tetrahymena eukaryotic translation elongation factor 1A (eEF1A) bundles filamentous actin through dimer formation. J Biochem (Tokyo) 140:393–399. https://doi.org/10.1093/jb/mvj169
Calì T, Ottolini D, Negro A, Brini M (2012) α-Synuclein controls mitochondrial calcium homeostasis by enhancing endoplasmic reticulum–mitochondria interactions. J Biol Chem 287:17914–17929. https://doi.org/10.1074/jbc.M111.302794
Calo L, Wegrzynowicz M, Santivañez-Perez J, Grazia Spillantini M (2016) Synaptic failure and α-synuclein. Mov Disord 31:169–177. https://doi.org/10.1002/mds.26479
Caraveo G, Auluck PK, Whitesell L, Chung CY, Baru V, Mosharov EV, Yan X, Ben-Johny M, Soste M, Picotti P, Kim H, Caldwell KA, Caldwell GA, Sulzer D, Yue DT, Lindquist S (2014) Calcineurin determines toxic versus beneficial responses to -synuclein. Proc Natl Acad Sci 111:E3544–E3552. https://doi.org/10.1073/pnas.1413201111
Carpenter AE, Jones TR, Lamprecht MR, Clarke C, Kang IH, Friman O, Guertin DA, Chang JH, Lindquist RA, Moffat J, Golland P, Sabatini DM (2006) Cell Profiler: image analysis software for identifying and quantifying cell phenotypes. Genome Biol 7:R100. https://doi.org/10.1186/gb-2006-7-10-r100
Cartelli D, Aliverti A, Barbiroli A, Santambrogio C, Ragg EM, Casagrande FVM, Cantele F, Beltramone S, Marangon J, De Gregorio C, Pandini V, Emanuele M, Chieregatti E, Pieraccini S, Holmqvist S, Bubacco L, Roybon L, Pezzoli G, Grandori R, Arnal I, Cappelletti G (2016) α-Synuclein is a novel microtubule dynamase. Sci Rep 6:33289. https://doi.org/10.1038/srep33289
Chai YJ, Sierecki E, Tomatis VM, Gormal RS, Giles N, Morrow IC, Xia D, Götz J, Parton RG, Collins BM, Gambin Y, Meunier FA (2016) Munc18-1 is a molecular chaperone for α-synuclein, controlling its self-replicating aggregation. J Cell Biol 214:705–718. https://doi.org/10.1083/jcb.201512016
Cho S-J, Jung J-S, Ko BH, Jin I, Moon IS (2004) Presence of translation elongation factor-1A (eEF1A) in the excitatory postsynaptic density of rat cerebral cortex. Neurosci Lett 366:29–33. https://doi.org/10.1016/j.neulet.2004.05.036
Cho S-J, Lee H-S, Dutta S, Seog D-H, Moon I-S (2012) Translation elongation factor-1A1 (eEF1A1) localizes to the spine by domain III. BMB Rep 45:227–232. https://doi.org/10.5483/BMBRep
Chuang S-M, Chen L, Lambertson D, Anand M, Kinzy TG, Madura K (2005) Proteasome-mediated degradation of cotranslationally damaged proteins involves translation elongation factor 1A. Mol Cell Biol 25:403–413. https://doi.org/10.1128/MCB.25.1.403-413.2005
Cohen LD, Zuchman R, Sorokina O, Müller A, Dieterich DC, Armstrong JD, Ziv T, Ziv NE (2013) Metabolic turnover of synaptic proteins: kinetics, interdependencies and implications for synaptic maintenance. PLoS ONE 8:e63191. https://doi.org/10.1371/journal.pone.0063191
De Robertis E, De Lores Rodriguez, Arnaiz G, Pellegrino De Iraldi A (1962) Isolation of synaptic vesicles from nerve endings of the rat brain. Nature 194:794–795
Delaidelli A, Jan A, Herms J, Sorensen PH (2019) Translational control in brain pathologies: biological significance and therapeutic opportunities. Acta Neuropathol (Berl) 137:535–555. https://doi.org/10.1007/s00401-019-01971-8
Di Sano F, Piacentini M (2012) Reticulon protein-1C: a new hope in the treatment of different neuronal diseases. Int J Cell Biol 2012:1–9. https://doi.org/10.1155/2012/651805
Diao J, Burré J, Vivona S, Cipriano DJ, Sharma M, Kyoung M, Südhof TC, Brunger AT (2013) Native α-synuclein induces clustering of synaptic-vesicle mimics via binding to phospholipids and synaptobrevin-2/VAMP2. eLife. https://doi.org/10.7554/eLife.00592
Dickson DW, Crystal HA, Bevona C, Honer W, Vincent I, Davies P (1995) Correlations of synaptic and pathological markers with cognition of the elderly. Neurobiol Aging 16:285–298. https://doi.org/10.1016/0197-4580(95)00013-5
Dieterich DC, Kreutz MR (2016) Proteomics of the synapse—a quantitative approach to neuronal plasticity. Mol Cell Proteom MCP 15:368–381. https://doi.org/10.1074/mcp.R115.051482
Emanuele M, Esposito A, Camerini S, Antonucci F, Ferrara S, Seghezza S, Catelani T, Crescenzi M, Marotta R, Canale C, Matteoli M, Menna E, Chieregatti E (2016) Exogenous alpha-synuclein alters pre- and post-synaptic activity by fragmenting lipid rafts. EBioMedicine 7:191–204. https://doi.org/10.1016/j.ebiom.2016.03.038
Fernández E, Collins MO, Uren RT, Kopanitsa MV, Komiyama NH, Croning MDR, Zografos L, Armstrong JD, Choudhary JS, Grant SGN (2009) Targeted tandem affinity purification of PSD-95 recovers core postsynaptic complexes and schizophrenia susceptibility proteins. Mol Syst Biol 5:269. https://doi.org/10.1038/msb.2009.27
Fortin DL (2004) Lipid rafts mediate the synaptic localization of α-synuclein. J Neurosci 24:6715–6723. https://doi.org/10.1523/JNEUROSCI.1594-04.2004
Fujimura M, Usuki F, Cheng J, Zhao W (2016) Prenatal low-dose methylmercury exposure impairs neurite outgrowth and synaptic protein expression and suppresses TrkA pathway activity and eEF1A1 expression in the rat cerebellum. Toxicol Appl Pharmacol 298:1–8. https://doi.org/10.1016/j.taap.2016.03.002
Fusco G, Pape T, Stephens AD, Mahou P, Costa AR, Kaminski CF, Kaminski Schierle GS, Vendruscolo M, Veglia G, Dobson CM, De Simone A (2016) Structural basis of synaptic vesicle assembly promoted by α-synuclein. Nat Commun 7:12563. https://doi.org/10.1038/ncomms12563
Garcia-Esparcia P, Hernández-Ortega K, Koneti A, Gil L, Delgado-Morales R, Castaño E, Carmona M, Ferrer I (2015) Altered machinery of protein synthesis is region- and stage-dependent and is associated with α-synuclein oligomers in Parkinson’s disease. Acta Neuropathol Commun 3:76. https://doi.org/10.1186/s40478-015-0257-4
Giustetto M, Hegde AN, Si K, Casadio A, Inokuchi K, Pei W, Kandel ER, Schwartz JH (2003) Axonal transport of eukaryotic translation elongation factor 1α mRNA couples transcription in the nucleus to long-term facilitation at the synapse. Proc Natl Acad Sci 100:13680–13685
Gray EG, Whittaker VP (1962) The isolation of nerve endings from brain: an electron-microscopic study of cell fragments derived by homogenization and centrifugation. J Anat 96:79–88
Gross SR, Kinzy TG (2005) Translation elongation factor 1A is essential for regulation of the actin cytoskeleton and cell morphology. Nat Struct Mol Biol 12:772–778. https://doi.org/10.1038/nsmb979
Guardia-Laguarta C, Area-Gomez E, Rub C, Liu Y, Magrane J, Becker D, Voos W, Schon EA, Przedborski S (2014) α-Synuclein is localized to mitochondria-associated ER membranes. J Neurosci 34:249–259. https://doi.org/10.1523/JNEUROSCI.2507-13.2014
Hafner A-S, Donlin-Asp PG, Leitch B, Herzog E, Schuman EM (2019) Local protein synthesis is a ubiquitous feature of neuronal pre- and postsynaptic compartments. Science. https://doi.org/10.1126/science.aau3644
Hashimoto K, Ishima T (2011) Neurite outgrowth mediated by translation elongation factor eEF1A1: a target for antiplatelet agent cilostazol. PLoS ONE 6:e17431. https://doi.org/10.1371/journal.pone.0017431
Herzog E, Nadrigny F, Silm K, Biesemann C, Helling I, Bersot T, Steffens H, Schwartzmann R, Nagerl UV, El Mestikawy S, Rhee J, Kirchhoff F, Brose N (2011) In vivo imaging of intersynaptic vesicle exchange using VGLUT1Venus knock-in mice. J Neurosci 31:15544–15559. https://doi.org/10.1523/JNEUROSCI.2073-11.2011
Hosp F, Mann M (2017) A primer on concepts and applications of proteomics in neuroscience. Neuron 96:558–571. https://doi.org/10.1016/j.neuron.2017.09.025
Hu Q, Wang G (2016) Mitochondrial dysfunction in Parkinson’s disease. Transl Neurodegener 5:14. https://doi.org/10.1186/s40035-016-0060-6
Huang DW, Sherman BT, Lempicki RA (2008) Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc 4:44–57. https://doi.org/10.1038/nprot.2008.211
Huang DW, Sherman BT, Lempicki RA (2009) Bioinformatics enrichment tools: paths toward the comprehensive functional analysis of large gene lists. Nucleic Acids Res 37:1–13. https://doi.org/10.1093/nar/gkn923
Iketani M, Iizuka A, Sengoku K, Kurihara Y, Nakamura F, Sasaki Y, Sato Y, Yamane M, Matsushita M, Nairn AC, Takamatsu K, Goshima Y, Takei K (2013) Regulation of neurite outgrowth mediated by localized phosphorylation of protein translational factor eEF2 in growth cones. Dev Neurobiol 73:230–246. https://doi.org/10.1002/dneu.22058
Kilkenny C, Browne WJ, Cuthill IC, Emerson M, Altman DG (2012) Improving bioscience research reporting: the ARRIVE guidelines for reporting animal research. Osteoarthr Cartil 20:256–260
Liu G, Tang J, Edmonds BT, Murray J, Levin S, Condeelis J (1996) F-actin sequesters elongation factor 1alpha from interaction with aminoacyl-tRNA in a pH-dependent reaction. J Cell Biol 135:953–963
Liu G, Wang P, Li X, Li Y, Xu S, Uéda K, Chan P, Yu S (2013) Alpha-synuclein promotes early neurite outgrowth in cultured primary neurons. J Neural Transm 120:1331–1343. https://doi.org/10.1007/s00702-013-0999-8
Logan T, Bendor J, Toupin C, Thorn K, Edwards RH (2017) α-Synuclein promotes dilation of the exocytotic fusion pore. Nat Neurosci 20:681–689. https://doi.org/10.1038/nn.4529
Lotharius J, Brundin P (2002) Pathogenesis of Parkinson’s disease: dopamine, vesicles and alpha-synuclein. Nat Rev Neurosci 3:932–942. https://doi.org/10.1038/nrn983
Luquet E, Biesemann C, Munier A, Herzog E (2017) Purification of synaptosome populations using fluorescence-activated synaptosome sorting. Methods Mol Biol Clifton NJ 1538:121–134. https://doi.org/10.1007/978-1-4939-6688-2_10
Ma T, Trinh MA, Wexler AJ, Bourbon C, Gatti E, Pierre P, Cavener DR, Klann E (2013) Suppression of eIF2α kinases alleviates Alzheimer’s disease-related plasticity and memory deficits. Nat Neurosci 16:1299–1305. https://doi.org/10.1038/nn.3486
Masliah E (2000) Dopaminergic loss and inclusion body formation in α-synuclein mice: implications for neurodegenerative disorders. Science 287:1265–1269. https://doi.org/10.1126/science.287.5456.1265
Mateyak MK, Kinzy TG (2010) eEF1A: thinking outside the ribosome. J Biol Chem 285:21209–21213. https://doi.org/10.1074/jbc.R110.113795
McClatchy DB, Fang G, Levey AI (2006) Elongation factor 1A family regulates the recycling of the M4 muscarinic acetylcholine receptor. Neurochem Res 31:975–988. https://doi.org/10.1007/s11064-006-9103-1
McInnes J, Wierda K, Snellinx A, Bounti L, Wang Y-C, Stancu I-C, Apóstolo N, Gevaert K, Dewachter I, Spires-Jones TL, De Strooper B, De Wit J, Zhou L, Verstreken P (2018) Synaptogyrin-3 mediates presynaptic dysfunction induced by Tau. Neuron 97:823–835.e8. https://doi.org/10.1016/j.neuron.2018.01.022
Moreno JA, Radford H, Peretti D, Steinert JR, Verity N, Martin MG, Halliday M, Morgan J, Dinsdale D, Ortori CA, Barrett DA, Tsaytler P, Bertolotti A, Willis AE, Bushell M, Mallucci GR (2012) Sustained translational repression by eIF2α-P mediates prion neurodegeneration. Nature 485:507–511. https://doi.org/10.1038/nature11058
Nakamura K, Nemani VM, Azarbal F, Skibinski G, Levy JM, Egami K, Munishkina L, Zhang J, Gardner B, Wakabayashi J, Sesaki H, Cheng Y, Finkbeiner S, Nussbaum RL, Masliah E, Edwards RH (2011) Direct membrane association drives mitochondrial fission by the Parkinson disease-associated protein alpha-synuclein. J Biol Chem 286:20710–20726. https://doi.org/10.1074/jbc.M110.213538
Nakayama K, Suzuki Y, Yazawa I (2012) Binding of neuronal α-synuclein to β-III tubulin and accumulation in a model of multiple system atrophy. Biochem Biophys Res Commun 417:1170–1175. https://doi.org/10.1016/j.bbrc.2011.12.092
Nemani VM, Lu W, Berge V, Nakamura K, Onoa B, Lee MK, Chaudhry FA, Nicoll RA, Edwards RH (2010) Increased expression of α-synuclein reduces neurotransmitter release by inhibiting synaptic vesicle reclustering after endocytosis. Neuron 65:66–79. https://doi.org/10.1016/j.neuron.2009.12.023
Park J, Park Y, Ryu I, Choi M-H, Lee HJ, Oh N, Kim K, Kim KM, Choe J, Lee C, Baik J-H, Kim YK (2017) Misfolded polypeptides are selectively recognized and transported toward aggresomes by a CED complex. Nat Commun 8:15730. https://doi.org/10.1038/ncomms15730
Petroulakis E, Wang E (2002) Nerve growth factor specifically stimulates translation of eukaryotic elongation factor 1A-1 (eEF1A-1) mRNA by recruitment to polyribosomes in PC12 cells. J Biol Chem 277:18718–18727. https://doi.org/10.1074/jbc.M111782200
Picconi B, Piccoli G, Calabresi P (2012) Synaptic dysfunction in Parkinson’s disease. Adv Exp Med Biol 970:553–572. https://doi.org/10.1007/978-3-7091-0932-8_24
Plotegher N, Kumar D, Tessari I, Brucale M, Munari F, Tosatto L, Belluzzi E, Greggio E, Bisaglia M, Capaldi S, Aioanei D, Mammi S, Monaco HL, Samo B, Bubacco L (2014) The chaperone-like protein 14-3-3η interacts with human α-synuclein aggregation intermediates rerouting the amyloidogenic pathway and reducing α-synuclein cellular toxicity. Hum Mol Genet 23:5615–5629. https://doi.org/10.1093/hmg/ddu275
Prots I, Veber V, Brey S, Campioni S, Buder K, Riek R, Bohm KJ, Winner B (2013) Synuclein oligomers impair neuronal microtubule-kinesin interplay. J Biol Chem 288:21742–21754. https://doi.org/10.1074/jbc.M113.451815
Ruest L-B, Marcotte R, Wang E (2002) Peptide elongation factor eEF1A-2/S1 expression in cultured differentiated myotubes and its protective effect against caspase-3-mediated apoptosis. J Biol Chem 277:5418–5425. https://doi.org/10.1074/jbc.M110685200
Schreiner D, Savas JN, Herzog E, Brose N, de Wit J (2017) Synapse biology in the ’circuit-age’-paths toward molecular connectomics. Curr Opin Neurobiol 42:102–110. https://doi.org/10.1016/j.conb.2016.12.004
Scott D, Roy S (2012) α-Synuclein inhibits intersynaptic vesicle mobility and maintains recycling-pool homeostasis. J Neurosci 32:10129–10135. https://doi.org/10.1523/JNEUROSCI.0535-12.2012
Sharma K, Schmitt S, Bergner CG, Tyanova S, Kannaiyan N, Manrique-Hoyos N, Kongi K, Cantuti L, Hanisch U-K, Philips M-A, Rossner MJ, Mann M, Simons M (2015) Cell type- and brain region-resolved mouse brain proteome. Nat Neurosci 18:1819–1831. https://doi.org/10.1038/nn.4160
Shigeoka T, Jung H, Jung J, Turner-Bridger B, Ohk J, Lin JQ, Amieux PS, Holt CE (2016) Dynamic axonal translation in developing and mature visual circuits. Cell 166:181–192. https://doi.org/10.1016/j.cell.2016.05.029
Spillantini MG, Schmidt ML, Lee VM, Trojanowski JQ, Jakes R, Goedert M (1997) Alpha-synuclein in Lewy bodies. Nature 388:839–840. https://doi.org/10.1038/42166
Suzuki Y, Jin C, Iwase T, Yazawa I (2014) III Tubulin fragments inhibit—synuclein accumulation in models of multiple system atrophy. J Biol Chem 289:24374–24382. https://doi.org/10.1074/jbc.M114.557215
Taylor AM, Berchtold NC, Perreau VM, Tu CH, Li Jeon N, Cotman CW (2009) Axonal mRNA in uninjured and regenerating cortical mammalian axons. J Neurosci 29:4697–4707. https://doi.org/10.1523/JNEUROSCI.6130-08.2009
Terry RD, Masliah E, Salmon DP, Butters N, DeTeresa R, Hill R, Hansen LA, Katzman R (1991) Physical basis of cognitive alterations in Alzheimer’s disease: synapse loss is the major correlate of cognitive impairment. Ann Neurol 30:572–580. https://doi.org/10.1002/ana.410300410
Tsokas P, Grace EA, Chan P, Ma T, Sealfon SC, Iyengar R, Landau EM, Blitzer RD (2005) Local protein synthesis mediates a rapid increase in dendritic elongation factor 1A after induction of late long-term potentiation. J Neurosci 25:5833–5843. https://doi.org/10.1523/JNEUROSCI.0599-05.2005
Vargas KJ, Makani S, Davis T, Westphal CH, Castillo PE, Chandra SS (2014) Synucleins regulate the kinetics of synaptic vesicle endocytosis. J Neurosci 34:9364–9376. https://doi.org/10.1523/JNEUROSCI.4787-13.2014
Vizcaíno JA, Csordas A, del-Toro N, Dianes JA, Griss J, Lavidas I, Mayer G, Perez-Riverol Y, Reisinger F, Ternent T, Xu Q-W, Wang R, Hermjakob H (2016) 2016 update of the PRIDE database and its related tools. Nucleic Acids Res 44:D447–D456. https://doi.org/10.1093/nar/gkv1145
Walker L, Stefanis L, Attems J (2019) Clinical and neuropathological differences between Parkinson’s disease, Parkinson’s disease dementia and dementia with Lewy bodies—current issues and future directions. J Neurochem. https://doi.org/10.1111/jnc.14698
Wang X, Huang T, Bu G, Xu H (2014) Dysregulation of protein trafficking in neurodegeneration. Mol Neurodegener 9:31
Whittaker VP, Michaelson I, Kirkland RJA (1964) The separation of synaptic vesicles from nerve-ending particles (synaptosomes’). Biochem J 90:293
Wong YC, Krainc D (2017) α-synuclein toxicity in neurodegeneration: mechanism and therapeutic strategies. Nat Med 23:1–13. https://doi.org/10.1038/nm.4269
Xu J, Wu X-S, Sheng J, Zhang Z, Yue H-Y, Sun L, Sgobio C, Lin X, Peng S, Jin Y, Gan L, Cai H, Wu L-G (2016) α-Synuclein mutation inhibits endocytosis at mammalian central nerve terminals. J Neurosci 36:4408–4414. https://doi.org/10.1523/JNEUROSCI.3627-15.2016
Yang F, Demma M, Warren V, Dharmawardhane S, Condeelis J (1990) Identification of an actin-binding protein from dictyostelium as elongation factor 1a. Nature 347:494–496. https://doi.org/10.1038/347494a0
Acknowledgements
We thank Sarah Hanselka, Katharina Bayer, Michael Schmidt, Dr. Christelle Martin, Melissa Deshors, Dr. Norbert Buresch (Neurobiobank Munich), Dr. Vincent Pitard (Flow cytometry facility, CNRS UMS 3427, INSERM US 005, Univ. Bordeaux), Patrice Mascalchi (Bordeaux Imaging Center, CNRS, INSERM, Univ. Bordeaux) and the Biochemistry and biophysics facility of Bordeaux Neurocampus (CNRS, INSERM, Univ. Bordeaux) for their excellent technical support and animal care. We are also thankful towards Stephan Müller for his expertise in proteomics and advice on our data.
Funding
This work was funded by the Munich Cluster for Systems Neurology SyNergy (EXC1010) to SB, SC and JH; the German Academic Exchange Service (DAAD) to SB; the French Agence Nationale de la Recherche (ANR-12-JSV4-0005-01VGLUT-IQ and ANR-10-LABX-43 BRAIN) to EH; the Fondation pour la Recherche Médicale (ING20150532192) to EH and the CNRS PICS program to EH.
Author information
Authors and Affiliations
Contributions
SB performed design of the experiment, subcellular fractioning, FASS sorting, validation of results in mouse and human tissue, bioinformatics and interpretation of results and wrote the manuscript. MFA provided expertise and performed subcellular fractioning, FASS sorting and Western blotting with SB. FP performed programming for image analysis. MMD performed bioinformatic analyses. MMD, VCR and TA selected human tissue and provided neuropathological expertise. ML performed EM experiments and EM data analysis. SCl performed mass spectrometry and analysis of the MS raw data. EH performed STED microscopy. SCr and LS provided technical support. VCR, MMD, MFA, EH and JH helped with manuscript preparation. EH and JH supervised the study, contributed to conception, design and manuscript writing and provided financial support and final approval of the manuscript.
Corresponding authors
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Ethical approval
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Blumenstock, S., Angelo, M.F., Peters, F. et al. Early defects in translation elongation factor 1α levels at excitatory synapses in α-synucleinopathy. Acta Neuropathol 138, 971–986 (2019). https://doi.org/10.1007/s00401-019-02063-3
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00401-019-02063-3