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Acta Neuropathol. 2019 Dec;138(6):971-986. doi: 10.1007/s00401-019-02063-3. Epub 2019 Aug 26.

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

Author information

1
Center for Neuropathology and Prion Research, Ludwig-Maximilians University, Munich, Germany.
2
German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.
3
Munich Cluster of Systems Neurology (SyNergy), Munich, Germany.
4
Department Molecules-Signaling-Development, Max Planck Institute of Neurobiology, Martinsried, Germany.
5
Université de Bordeaux, Interdisciplinary Institute for Neuroscience, UMR5297, 33000, Bordeaux, France.
6
CNRS, Interdisciplinary Institute for Neuroscience, UMR5297, 33000, Bordeaux, France.
7
Department of Biology I, Biozentrum Ludwig-Maximilians University, Munich, Germany.
8
Department of Psychiatry and Psychotherapy, University Hospital, Ludwig-Maximilians University, Munich, Germany.
9
Plateforme Proteome, Centre Génomique Fonctionnelle de Bordeaux, Université de Bordeaux, Bordeaux, France.
10
Université de Bordeaux, Interdisciplinary Institute for Neuroscience, UMR5297, 33000, Bordeaux, France. etienne.herzog@u-bordeaux.fr.
11
CNRS, Interdisciplinary Institute for Neuroscience, UMR5297, 33000, Bordeaux, France. etienne.herzog@u-bordeaux.fr.
12
Center for Neuropathology and Prion Research, Ludwig-Maximilians University, Munich, Germany. jochen.herms@med.uni-muenchen.de.
13
German Center for Neurodegenerative Diseases (DZNE), Munich, Germany. jochen.herms@med.uni-muenchen.de.
14
Munich Cluster of Systems Neurology (SyNergy), Munich, Germany. jochen.herms@med.uni-muenchen.de.

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; FASS; Lewy body dementia; Proteomics; Synapse

PMID:
31451907
DOI:
10.1007/s00401-019-02063-3

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