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Published on: August 16, 2020
A novel function of FAF1, which induces dopaminergic neuronal death through cell-to-cell transmission
Gyeongrin Park1, Bok-Seok Kim1, Eunhee Kim2
1Department of Biological Sciences, Chungnam National University, 99 Daehak-ro, Yuseong-gu, Daejeon, 34134, South Korea.
Background:
Fas-associated factor 1 (FAF1) has been implicated in Parkinson's disease (PD) and activates the cell death machinery in the cytosol. However, the presence of extracellular FAF1 has not been studied.
Methods:
Serum-free conditioned medium (CM) from FAF1-transfected SH-SY5Y cells was concentrated and analyzed by western blotting. Exosomes were isolated from CM by ultracentrifugation and analyzed by western blotting, electron microscopy and nanoparticle tracking analysis. Soluble FAF1 from CM was immunodepleted using anti-FAF1 antibody. Transmission of secreted FAF1 was examined by transwell assay under a confocal microscope. CM-induced cell death was determined by measuring propidium iodide (PI) uptake using a flow cytometer.
Results:
FAF1 was secreted from SH-SY5Y cells via exocytosis and brefeldin A (BFA)-resistant secretory pathways. Furthermore, FAF1 was secreted as a vesicle-free form and a genuine exosome cargo in the lumen of exosomes. In addition, FAF1 increased the number of exosomes, suggesting a regulatory role in exosome biogenesis. Extracellular FAF1 was transmitted via endocytosis to neighboring cells, where it induced cell death through apoptotic and necrotic pathways.
Conclusions:
This study presents a novel route by which FAF1 induces neuronal death through cell-to-cell transmission. Video Abstract.
Insights
Fas-associated factor 1 (FAF1) is secreted by cells and transmitted to neighboring cells, where it induces neuronal death. This extracellular FAF1, found in exosomes and soluble forms, contributes to Parkinson's disease pathology.
Area of Science:
- Cell biology
- Neuroscience
- Molecular biology
Background:
- Fas-associated factor 1 (FAF1) is linked to Parkinson's disease (PD) and cytosolic cell death.
- The extracellular presence and function of FAF1 remain uninvestigated.
Purpose of the Study:
- To investigate the secretion and extracellular role of FAF1.
- To determine if extracellular FAF1 contributes to neuronal cell death.
Main Methods:
- FAF1 secretion from SH-SY5Y cells was analyzed.
- Exosomes were isolated and characterized using ultracentrifugation, western blotting, electron microscopy, and nanoparticle tracking analysis.
- Cell death was assessed via propidium iodide uptake using flow cytometry.
Main Results:
- FAF1 is secreted via exosome-dependent and independent pathways, existing as both exosomal cargo and soluble forms.
- Extracellular FAF1 is taken up by neighboring cells through endocytosis.
- FAF1 induces cell death via apoptotic and necrotic pathways and may regulate exosome biogenesis.
Conclusions:
- Extracellular FAF1 induces neuronal death through cell-to-cell transmission.
- This novel mechanism highlights a potential role for extracellular FAF1 in neurodegenerative diseases like PD.
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