Unconventional secretion of α-synuclein mediated by palmitoylated DNAJC5 oligomers
- Howard Hughes Medical Institute, University of California, Berkeley, United States
- University of California, Berkeley, United States
- University of California, San Francisco, United States
- University of Oxford, United Kingdom
Abstract
Alpha-synuclein (α-syn), a major component of Lewy bodies found in Parkinson's disease (PD) patients, has been found exported outside of cells and may mediate its toxicity via cell-to-cell transmission. Here, we reconstituted soluble, monomeric a-syn secretion by the expression of DnaJ homolog subfamily C member 5 (DNAJC5) in HEK293T cells. DNAJC5 undergoes palmitoylation and anchors on the membrane. Palmitoylation is essential for DNAJC5-induced α-syn secretion, and the secretion is not limited by substrate size or unfolding. Cytosolic α-syn is actively translocated and sequestered in an endosomal membrane compartment in a DNAJC5-dependent manner. Reduction of α-syn secretion caused by a palmitoylation-deficient mutation in DNAJC5 can be reversed by a membrane-targeting peptide fusion-induced oligomerization of DNAJC5. The secretion of endogenous α-syn mediated by DNAJC5 is also found in a human neuroblastoma cell line, SH-SY5Y, differentiated into neurons in the presence of retinoic acid, and in human induced pluripotent stem cell-derived midbrain dopamine neurons. We propose that DNAJC5 forms a palmitoylated oligomer to accommodate and export α-syn.
Data availability
All data generated or analysed during this study are included in the manuscript and supporting file; Source Data files have been provided for all the Figures.
Article and author information
Author details
Nancy C Hernandez Villegas
Funding
Howard Hughes Medical Institute
- Randy Schekman
NIH Biology and Biotechnology of Cell and Gene Therapy Training Program (NIH training program T32GM139780)
- Nancy C Hernandez Villegas
Aligning Science Across Parkinson's (ASAP-020370)
- Richard Wade-Martins
- Randy Schekman
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2023, Wu et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Unconventional secretion of α-synuclein mediated by palmitoylated DNAJC5 oligomers
eLife 12:e85837.
https://doi.org/10.7554/eLife.85837
