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01-12-2019 | Dementia | Original Paper

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

Authors: Sonja Blumenstock, Maria Florencia Angelo, Finn Peters, Mario M. Dorostkar, Viktoria C. Ruf, Manja Luckner, Sophie Crux, Lenka Slapakova, Thomas Arzberger, Stéphane Claverol, Etienne Herzog, Jochen Herms

Published in: Acta Neuropathologica | Issue 6/2019

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.

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Title: Early defects in translation elongation factor 1α levels at excitatory synapses in α-synucleinopathy
Authors: Sonja Blumenstock
Maria Florencia Angelo
Finn Peters
Mario M. Dorostkar
Viktoria C. Ruf
Manja Luckner
Sophie Crux
Lenka Slapakova
Thomas Arzberger
Stéphane Claverol
Etienne Herzog
Jochen Herms
Publication date: 01-12-2019
Publisher: Springer Berlin Heidelberg
Keywords: Dementia
Dementia
Published in: Acta Neuropathologica / Issue 6/2019
Print ISSN: 0001-6322
Electronic ISSN: 1432-0533
DOI: https://doi.org/10.1007/s00401-019-02063-3

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

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

Abstract

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Springer Medicine

Abstract

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