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

• Published in: Nature communications Vol. 5; no. 1; p. 4755
• Main Authors: Bae, Eun-Jin, Yang, Na-Young, Song, Miyoung, Lee, Cheol Soon, Lee, Jun Sung, Jung, Byung Chul, Lee, He-Jin, Kim, Seokjoong, Masliah, Eliezer, Sardi, Sergio Pablo, Lee, Seung-Jae
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 26.08.2014
• Subjects: 13; 13/1; 13/106; 13/51; 13/89; 14/19; 14/28; 38/70; 631/378/1689/1718; 631/80/470/2284; 692/420; 82; alpha-Synuclein - genetics; alpha-Synuclein - metabolism; Animals; beta-Glucosidase - genetics; beta-Glucosidase - metabolism; Cell Communication; Cell Line; Exocytosis; Gene Knockout Techniques; Humanities and Social Sciences; Humans; Lysosomes - metabolism; Lysosomes - pathology; Mice, Transgenic; multidisciplinary; Parkinson Disease - metabolism; Parkinson Disease - pathology; Protein Transport; Science; Science (multidisciplinary)
• ISSN: 2041-1723; 2041-1723
• 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. Transmission of alpha-synuclein aggregates between neurons has been observed in animal models of Parkinson’s disease, however, the mechanism of transmission remains unclear. Bae et al . report that a cycle of uptake, co-aggregation and exocytosis is enhanced by loss of glucocerebrosidase activity.