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

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cerebral Cortex / metabolism
  • Cerebral Cortex / pathology
  • Computational Biology
  • Disease Models, Animal
  • Disks Large Homolog 4 Protein / metabolism
  • Female
  • Male
  • Mice, Transgenic
  • Neuropil / metabolism
  • Neuropil / pathology
  • Peptide Elongation Factor 1 / metabolism*
  • Proteome
  • Synapses / metabolism*
  • Synapses / pathology
  • Synucleinopathies / metabolism*
  • Synucleinopathies / pathology
  • alpha-Synuclein / genetics
  • alpha-Synuclein / metabolism


  • Disks Large Homolog 4 Protein
  • Dlg4 protein, mouse
  • EEF1A1 protein, human
  • Eef1a1 protein, mouse
  • Peptide Elongation Factor 1
  • Proteome
  • SNCA protein, human
  • alpha-Synuclein