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- Title
Unconventional secretion of a-synuclein mediated by palmitoylated DNAJC5 oligomers.
- Authors
Shenjie Wu; Villegas, Nancy C. Hernandez; Sirkis, Daniel W.; Thomas-Wright, Iona; Wade-Martins, Richard; Schekman, Randy
- Abstract
Alpha-synuclein (a-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 a-syn secretion, and the secretion is not limited by substrate size or unfolding. Cytosolic a-syn is actively translocated and sequestered in an endosomal membrane compartment in a DNAJC5-dependent manner. Reduction of a-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 a-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 a-syn.
- Subjects
SECRETION; PARKINSON'S disease; OLIGOMERS; PEPTIDES; PALMITOYLATION
- Publication
eLife, 2023, p1
- ISSN
2050-084X
- Publication type
Article
- DOI
10.7554/eLife.85837