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

Abstract

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.

• Authors: Eun-Jin Bae, Na-Young Yang, Miyoung Song, Cheol Soon Lee, Jun Sung Lee, Byung Chul Jung, He-Jin Lee, Seokjoong Kim, Eliezer Masliah, Sergio Pablo Sardi, Seung-Jae Lee
• Journal: Nature communications (Nat Commun) Vol. 5 Pg. 4755 (Aug 26 2014) ISSN: 2041-1723 [Electronic] England
• PMID: 25156829 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

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

Topics

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