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

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 and Herms, Jochen (2019): Early defects in translation elongation factor 1 alpha levels at excitatory synapses in alpha-synucleinopathy. In: Acta Neuropathologica, Vol. 138, No. 6: pp. 971-986

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.

• Item Type: Journal article
• Faculties: Medicine; Biology > Department Biology I; Medicine > Munich Cluster for Systems Neurology (SyNergy)
• Subjects: 600 Technology > 610 Medicine and health; 500 Science > 570 Life sciences; biology
• ISSN: 0001-6322
• Language: English
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 390857198