1. Unconventional secretion of α-synuclein mediated by palmitoylated DNAJC5 oligomers.
- Author
-
Wu, Shenjie, Hernandez Villegas, Nancy C, Sirkis, Daniel W, Thomas-Wright, Iona, Wade-Martins, Richard, and Schekman, Randy
- Subjects
Humans ,Neuroblastoma ,Parkinson Disease ,alpha-Synuclein ,HEK293 Cells ,Dopaminergic Neurons ,DNAJC5 ,alpha-synuclein ,cell biology ,human ,neuroscience ,palmitoylation ,parkinson's disease ,trafficking ,unconventional secretion ,Neurodegenerative ,Parkinson's Disease ,Neurosciences ,Brain Disorders ,Stem Cell Research ,Aetiology ,2.1 Biological and endogenous factors ,Neurological ,Human ,Biochemistry and Cell Biology - 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.
- Published
- 2023