Glucocerebrosidase depletion enhances cell-to-cell transmission of α-synuclein

Nat Commun. 2014 Aug 26:5:4755. doi: 10.1038/ncomms5755.


Deposition of α-synuclein aggregates occurs widely in the central and peripheral nervous systems in Parkinson's disease (PD). Although recent evidence has suggested that cell-to-cell transmission of α-synuclein aggregates is associated with the progression of PD, the mechanism by which α-synuclein aggregates spread remains undefined. Here, we show that α-synuclein aggregates are transmitted from cell to cell through a cycle involving uptake of external aggregates, co-aggregation with endogenous α-synuclein and exocytosis of the co-aggregates. Moreover, we find that glucocerebrosidase depletion, which has previously been strongly associated with PD and increased cognitive impairment, promotes propagation of α-synuclein aggregates. These studies define how α-synuclein aggregates spread among neuronal cells and may provide an explanation for how glucocerebrosidase mutations increase the risk of developing PD and other synucleinopathies.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Communication
  • Cell Line
  • Exocytosis
  • Gene Knockout Techniques
  • Glucosylceramidase
  • Humans
  • Lysosomes / metabolism
  • Lysosomes / pathology
  • Mice, Transgenic
  • Parkinson Disease / metabolism
  • Parkinson Disease / pathology*
  • Protein Transport
  • alpha-Synuclein / genetics
  • alpha-Synuclein / metabolism*
  • beta-Glucosidase / genetics*
  • beta-Glucosidase / metabolism


  • alpha-Synuclein
  • beta-Glucosidase
  • GBA2 protein, human
  • Glucosylceramidase