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Blumenstock, Sonja; Angelo, Maria Florencia; Peters, Finn; Dorostkar, Mario M.; Ruf, Viktoria C.; Luckner, Manja; Crux, Sophie; Slapakova, Lenka; Arzberger, Thomas; Claverol, Stephane; Herzog, Etienne und Herms, Jochen (2019): Early defects in translation elongation factor 1 alpha levels at excitatory synapses in alpha-synucleinopathy. In: Acta Neuropathologica, Bd. 138, Nr. 6: S. 971-986

Volltext auf 'Open Access LMU' nicht verfügbar.

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 alpha-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-alpha S) 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-alpha S 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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