Unconventional secretion of α-synuclein mediated by palmitoylated DNAJC5 oligomers
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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 α-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.
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- Authors
- Wu, S., Hernandez Villegas, N. C., Sirkis, D. W., Thomas-Wright, I., Wade-Martins, R., & Schekman, R.
- Affiliations
- Howard Hughes Medical Institute (US)
- Helen Wills Neuroscience Institute, University of California, Berkeley
- University of California, San Francisco (US)
- University of Oxford (GB)
- Oxford Parkinson’s Disease Centre, Department of Physiology, Anatomy and Genetics and Kavli Institute for Nanoscience Discovery, University of Oxford
- Corresponding author
- Schekman, Randy
- Venue
- eLife
- Publisher
- eLife Sciences Publications, Ltd
- Published
- 2023-01-10
- Volume
- 12
- ISSN
- 2050-084X (ISSN-L)
- PMC
- PMC9876576
- OpenAlex
- W4313988037
- Cited by
- 52
- References
- 6
- Citations by year
- 2026: 15 · 2025: 21 · 2024: 9 · 2023: 3 · 2022: 4
- FWCI
- 8.12
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- eLife (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Howard Hughes Medical Institute
- NIH Biology and Biotechnology of Cell and Gene Therapy Training Program (NIH training program T32GM139780)
- Aligning Science Across Parkinson's (ASAP-020370)
- Topics
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Keywords
- alpha-synuclein, DNAJC5, palmitoylation, unconventional secretion, protein oligomerization, Parkinson's disease, Lewy bodies, cell-to-cell transmission, membrane-targeting peptides, dopaminergic neurons, iPSC-derived neurons, neuroblastoma cells
- MeSH terms
- Humans, Membrane Proteins, Neuroblastoma, Parkinson Disease, HSP40 Heat-Shock Proteins, alpha-Synuclein, HEK293 Cells, Dopaminergic Neurons
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