Endosulfine-alpha inhibits membrane-induced α-synuclein aggregation and protects against α-synuclein neurotoxicity

Acta Neuropathol Commun. 2017 Jan 10;5(1):3. doi: 10.1186/s40478-016-0403-7.


Neuropathological and genetic findings suggest that the presynaptic protein α-synuclein (aSyn) is involved in the pathogenesis of synucleinopathy disorders, including Parkinson's disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy. Evidence suggests that the self-assembly of aSyn conformers bound to phospholipid membranes in an aggregation-prone state plays a key role in aSyn neurotoxicity. Accordingly, we hypothesized that protein binding partners of lipid-associated aSyn could inhibit the formation of toxic aSyn oligomers at membrane surfaces. To address this hypothesis, we characterized the protein endosulfine-alpha (ENSA), previously shown to interact selectively with membrane-bound aSyn, in terms of its effects on the membrane-induced aggregation and neurotoxicity of two familial aSyn mutants, A30P and G51D. We found that wild-type ENSA, but not the non-aSyn-binding S109E variant, interfered with membrane-induced aSyn self-assembly, aSyn-mediated vesicle disruption and aSyn neurotoxicity. Immunoblotting analyses revealed that ENSA was down-regulated in the brains of synucleinopathy patients versus non-diseased individuals. Collectively, these results suggest that ENSA can alleviate neurotoxic effects of membrane-bound aSyn via an apparent chaperone-like activity at the membrane surface, and a decrease in ENSA expression may contribute to aSyn neuropathology in synucleinopathy disorders. More generally, our findings suggest that promoting interactions between lipid-bound, amyloidogenic proteins and their binding partners is a viable strategy to alleviate cytotoxicity in a range of protein misfolding disorders.

Keywords: Endosulfine-alpha; Neurodegeneration; Parkinson’s disease; Synucleinopathy; α-Synuclein.

Publication types

  • Multicenter Study

MeSH terms

  • Adenoviridae
  • Aged
  • Aged, 80 and over
  • Animals
  • Brain / drug effects
  • Brain / metabolism
  • Brain / pathology
  • Cell Membrane / drug effects*
  • Cell Membrane / metabolism
  • Cells, Cultured
  • Cohort Studies
  • Dopaminergic Neurons / drug effects
  • Dopaminergic Neurons / metabolism
  • Dopaminergic Neurons / pathology
  • Escherichia coli
  • Female
  • HEK293 Cells
  • Humans
  • Intercellular Signaling Peptides and Proteins
  • Lewy Body Disease / metabolism
  • Lewy Body Disease / pathology
  • Male
  • Middle Aged
  • Neuroprotective Agents / metabolism
  • Neuroprotective Agents / pharmacology*
  • Peptides / metabolism
  • Peptides / pharmacology*
  • Protein Aggregation, Pathological / drug therapy*
  • Protein Aggregation, Pathological / metabolism
  • Rats, Sprague-Dawley
  • Recombinant Proteins / drug effects
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Unilamellar Liposomes / chemistry
  • alpha-Synuclein / drug effects*
  • alpha-Synuclein / genetics
  • alpha-Synuclein / metabolism


  • Intercellular Signaling Peptides and Proteins
  • Neuroprotective Agents
  • Peptides
  • Recombinant Proteins
  • Unilamellar Liposomes
  • alpha-Synuclein
  • endosulfine