Unconventional secretion of α-synuclein mediated by palmitoylated DNAJC5 oligomers

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...

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Bibliographic Details
Published in:eLife 2023-01, Vol.12
Main Authors: Wu, Shenjie, Hernandez Villegas, Nancy C, Sirkis, Daniel W, Thomas-Wright, Iona, Wade-Martins, Richard, Schekman, Randy
Format: Article
Language:English
Subjects:
alpha-synuclein
alpha-Synuclein - metabolism
Cell Biology
Cell differentiation
Cells
DNAJC5
Dopaminergic Neurons - metabolism
Fractionation
HEK293 Cells
Humans
Lewy bodies
Membrane fusion
Mesencephalon
Movement disorders
Mutation
Neuroblastoma - metabolism
Neurodegeneration
Neurodegenerative diseases
Neuroscience
Neurotoxicity
Oligomerization
Oligomers
Palmitoylation
Parkinson Disease - metabolism
Parkinson's disease
Pluripotency
Proteins
Retinoic acid
Secretion
Standard deviation
Stem cells
Synuclein
trafficking
unconventional secretion
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Summary: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.
ISSN:2050-084X
2050-084X
DOI:10.7554/eLife.85837