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学術論文

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

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Blumenstock, Sonja
Department: Molecules-Signaling-Development / Klein, MPI of Neurobiology, Max Planck Society;

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引用

Blumenstock, S., Angelo, M. F., Peters, F., Dorostkar, M. M., Ruf, V. C., Luckner, M., Crux, S., Slapakova, L., Arzberger, T., Claverol, S., Herzog, E., & Herms, J. (2019). Early defects in translation elongation factor 1 alpha levels at excitatory synapses in alpha-synucleinopathy. Acta Neuropathologica, 138(6), 971-986. doi:10.1007/s00401-019-02063-3.

要旨

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.