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Acta Neuropathologica

, Volume 138, Issue 6, pp 971–986 | Cite as

Early defects in translation elongation factor 1α levels at excitatory synapses in α-synucleinopathy

  • Sonja Blumenstock
  • Maria Florencia Angelo
  • Finn Peters
  • Mario M. Dorostkar
  • Viktoria C. Ruf
  • Manja Luckner
  • Sophie Crux
  • Lenka Slapakova
  • Thomas Arzberger
  • Stéphane Claverol
  • Etienne HerzogEmail author
  • Jochen HermsEmail author
Original Paper

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.

Keywords

Alpha-synuclein Elongation factor 1 alpha Synapse Proteomics Lewy body dementia FASS 

Notes

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.

Author 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.

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.

Compliance with ethical standards

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.

Supplementary material

401_2019_2063_MOESM1_ESM.xlsx (50 kb)
Supplementary file1 (XLSX 50 kb)
401_2019_2063_MOESM2_ESM.docx (3.6 mb)
Supplementary file2 (DOCX 3644 kb)

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Center for Neuropathology and Prion ResearchLudwig-Maximilians UniversityMunichGermany
  2. 2.German Center for Neurodegenerative Diseases (DZNE)MunichGermany
  3. 3.Université de Bordeaux, Interdisciplinary Institute for Neuroscience, UMR5297BordeauxFrance
  4. 4.CNRS, Interdisciplinary Institute for Neuroscience, UMR5297BordeauxFrance
  5. 5.Department of Biology IBiozentrum Ludwig-Maximilians UniversityMunichGermany
  6. 6.Department of Psychiatry and Psychotherapy, University HospitalLudwig-Maximilians UniversityMunichGermany
  7. 7.Plateforme Proteome, Centre Génomique Fonctionnelle de BordeauxUniversité de BordeauxBordeauxFrance
  8. 8.Munich Cluster of Systems Neurology (SyNergy)MunichGermany
  9. 9.Department Molecules-Signaling-DevelopmentMax Planck Institute of NeurobiologyMartinsriedGermany

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