Extracellular vesicle-mediated release of bis(monoacylglycerol)phosphate is regulated by LRRK2 and glucocerebrosidase activity
- Departament de Biomedicina, Unitat de Biologia Cel·lular, Facultat de Medicina i Ciències de la Salut, Centre de Recerca Biomèdica CELLEX, Institut d’Investigacions Biomèdiques August Pi i Sunyer, Universitat de Barcelona, Spain
- NextCea Inc, United States
- Lab of Parkinson Disease and Other Neurodegenerative Movement Disorders, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Institut de Neurociències, Universitat de Barcelona, Spain
- Parkinson Disease and Movement Disorders Unit, Neurology Service, Institut Clínic de Neurociències, Hospital Clínic de Barcelona, Spain
- Department of Biochemistry, Stanford University, United States
- Department of Neurology, Northwestern University, United States
Figures
Figure 1
Alterations in antibody-accessible BMP and endolysosomal morphology in R1441G LRRK2 mouse embryonic fibroblast (MEF) cells.
(A) Confocal microscopy of endogenous BMP (yellow) and LAMP2 (magenta) immunofluorescence in wild-type (WT) and R1441G LRRK2 MEFs. Scale bar: 20 µm. Quantification of vesicular BMP intensity (B) and LAMP2 relative intensity (C) per cell area. Colored dots represent mean value from four independent experiments, and violin plots show the distribution of individual cell data. Significance determined by two-tailed paired t-test **p < 0.01, ***p < 0.001. (D) Representative transmission electron microscopy (TEM) images of multivesicular endosomes (MVE) from WT and R1441G LRRK2 MEFs. MVB periphery highlighted in yellow. Scale bar: 250 nm. (E) MVE area (µm2) quantification in WT and R1441G LRRK2 mutant cells. Colored dots represent mean values from 3 independent experiments and violin plots show the distribution of individual cell data (35–45 cells/group). (F) Quantification of intraluminal vesicles (ILVs) per MVE in WT and R1441G LRRK2 MEF cells. The number of ILVs per MVE is binned in three groups and plotted as a percentage of MVE from the total population of each experiment independently. Data from 3 independent experiments (mean ± SEM). Significance determined by two-tailed unpaired t-test (E) and ordinary two-way ANOVA, uncorrected Fisher’s LSD (F). *p < 0.05, ****p < 0.0001.
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Figure 1—source data 1
IF images in panel A.
- https://cdn.elifesciences.org/articles/106330/elife-106330-fig1-data1-v1.zip
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Figure 1—source data 2
TEM images in panel D.
- https://cdn.elifesciences.org/articles/106330/elife-106330-fig1-data2-v1.zip
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Figure 1—source data 3
Plotted values in panels B, C, E, F.
- https://cdn.elifesciences.org/articles/106330/elife-106330-fig1-data3-v1.xlsx
Figure 2 with 1 supplement
LRRK2 and GCase activities modulate extracellular vesicle (EV) production.
(A) Whole cell lysates (WCL) from wild-type (WT) and R1441G LRRK2 mouse embryonic fibroblast (MEF) cells treated with 200 nM MLi-2 for 24 hr were analyzed by immunoblotting. Representative images of LAMP2, phospho-Rab10, and α-Tubulin levels are shown. Molecular weight marker mobility is shown in kDa. (B) Flow cytometry measurement of GCase activity using PFB-FDGlu fluorescent GCase substrate in WT and R1441G LRRK2 mutant MEF cells treated with 300 µM conduritol β-epoxide (CBE) for 24 hr. WCL and isolated EVs from WT and R1441G LRRK2 mutant MEF cells treated with 200 nM MLi-2 (C) or 300 µM CBE (G) for 48 hr were analyzed by immunoblotting. Representative images of LAMP2, Flotillin-1, and α-Tubulin levels are shown. Molecular weight marker mobility is shown in kDa. Immunoblots for LAMP2 and Flotillin-1 in EV fractions required longer exposure times to visualize clear signals across all conditions. Quantification of LAMP2 and Flotillin-1 levels relative to R1441G LRRK2 MEF cells in WCL (D, H) and isolated EVs (E, F, I, J). Data from 6 to 8 independent experiments (mean ± SEM). Significance determined by Kruskal–Wallis test followed by an uncorrected Dunn’s post hoc test compared to R1441G LRRK2 control *p < 0.05, **p < 0.01, ***p < 0.001; ns, not significant.
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Figure 2—source data 1
Uncropped blots.
- https://cdn.elifesciences.org/articles/106330/elife-106330-fig2-data1-v1.zip
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Figure 2—source data 2
Annotated uncropped blots.
- https://cdn.elifesciences.org/articles/106330/elife-106330-fig2-data2-v1.zip
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Figure 2—source data 3
Plotted values in panels D–F, H–J.
- https://cdn.elifesciences.org/articles/106330/elife-106330-fig2-data3-v1.xlsx
Figure 2—figure supplement 1
Further characterization of mouse embryonic fibroblast (MEF)-derived extracellular vesicle (EV) fractions.
(A–C) No significant differences in EV release between MLi-2/conduritol β-epoxide (CBE)-treated and untreated wild-type (WT) MEF cells. Quantification of LAMP2 and Flotillin-1 levels relative to WT control MEF cells in whole cell lysates (WCL) (A) and isolated EVs (B–C). Data from 7 to 8 independent experiments (mean ± SEM). Significance determined by ordinary one-way ANOVA, uncorrected Fisher’s LSD. (D–E) Characterization of WT or R1441G LRRK2 MEF-derived purified EVs by nanoparticle tracking analysis (NTA). (D) Representative plots of EV size distribution in each indicated condition. (E) Yield comparison of MEF-derived EVs from each indicated condition determined by NTA. Each colored dot represents an independent experiment.
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Figure 2—figure supplement 1—source data 1
Plotted values in panels A–C, E.
- https://cdn.elifesciences.org/articles/106330/elife-106330-fig2-figsupp1-data1-v1.xlsx
Figure 3 with 2 supplements
Targeted lipid pathway analysis of BMP abundance in cellular and isolated extracellular vesicle (EV) fractions.
Ultra-performance liquid chromatography–tandem mass spectrometry (UPLC–MS/MS) determination of BMP isoforms normalized to protein content from cells treated with 200 nM MLi-2 (A, B) or 300 µM conduritol β-epoxide (CBE) (C, D) for 48 hr. Data shown as fold change relative to untreated R1441G LRRK2 mouse embryonic fibroblast (MEF) cells. Only BMP isoforms that were detected are shown. (E) UPLC–MS/MS determination of BMP isoforms normalized to protein content in EVs isolated from cells treated with 200 nM MLi-2 or 300 µM CBE for 48 hr. Only BMP isoforms that were detected are shown. Data from 3 to 6 independent experiments (mean ± SEM). Significance determined by ordinary one-way ANOVA, uncorrected Fisher’s LSD (A–D) and one-way ANOVA with the Geisser–Greenhouse correction, uncorrected Fisher’s LSD (E). *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001.
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Figure 3—source data 1
Plotted values in panels A–E.
- https://cdn.elifesciences.org/articles/106330/elife-106330-fig3-data1-v1.xlsx
Figure 3—figure supplement 1
BMP levels are unchanged in wild-type (WT) mouse embryonic fibroblasts (MEFs) following MLi-2 or conduritol β-epoxide (CBE) treatment.
(A, B) No significant differences in cellular BMP levels between MLi-2/CBE-treated and untreated WT MEFs, as measured by ultra-performance liquid chromatography–tandem mass spectrometry (UPLC–MS/MS). (C) Table showing absolute values of UPLC–MS/MS measurements of cellular docosahexaenoyl (22:6)-, arachidonyl (20:4)-, oleoyl (18:1)-, and linoleyl (18:2)-BMP species from 3 representative independent experiments. (D) No significant differences in extracellular vesicle (EV)-associated BMP levels between MLi-2/CBE-treated and untreated WT MEF cells, as measured by UPLC–MS/MS. Lipidomics measurements of cellular (A, B) and EV-associated (D) BMP isoforms were normalized to protein content from cells treated with 200 nM MLi-2 or 300 µM CBE for 48 hr, or left untreated (ctrl). Data shown as fold change relative to WT control MEF cells. Only BMP isoforms that were detected are shown. Data from 6 to 7 independent experiments (mean ± SEM). Significance determined by ordinary two-tailed paired t-test; ns, not significant.
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Figure 3—figure supplement 1—source data 1
Plotted values in panels A, B, D.
- https://cdn.elifesciences.org/articles/106330/elife-106330-fig3-figsupp1-data1-v1.xlsx
Figure 3—figure supplement 2
Quantitative analysis of GCase substrates in mouse embryonic fibroblast (MEF) cells and extracellular vesicle (EV) fractions.
Lipidomic determination of glucosylceramide (GlcCer), galactosylceramide (GalCer), and glucosylsphingosine (GlcSph) isoforms normalized to protein content from wild-type (WT) and R1441G LRRK2 mutant MEF whole cell lysates (WCL) (A) and isolated EVs (B) treated with 300 µM conduritol β-epoxide (CBE) or 200 nM MLi-2 for 48 hr. Heatmap showing values as fold change relative to R1441G LRRK2 mutant MEF cell control. Only GlcCer, GalCer, and GlcSph isoforms that were detected are shown. Data from 3 to 9 independent experiments (mean ± SEM). Significance determined by ordinary two-way ANOVA, uncorrected Fisher’s LSD *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001.
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Figure 3—figure supplement 2—source data 1
Plotted values in panels A, B.
- https://cdn.elifesciences.org/articles/106330/elife-106330-fig3-figsupp2-data1-v1.xlsx
Figure 4
Inhibition of LRRK2 or GCase activities does not significantly impact BMP biosynthetic and catabolic rates.
(A) Schematic representation of the BMP metabolic labeling protocol with deuterated docosahexaenoic acid and 13C-labeled oleic acid. Wild-type (WT) and R1441G mutant mouse embryonic fibroblast (MEF) cells were incubated with a pulse of DHA-d5/OA-13C for 20 min, followed by a chase for different times. Cells were then collected for subsequent BMP lipidomic analysis. Structures of unlabeled (L) and isotope-labeled (H) fatty acids are shown in black or red, respectively. (B, C) Ultra-performance liquid chromatography–tandem mass spectrometry (UPLC–MS/MS) determination of BMP isoforms normalized to protein content from WT MEF cells and R1441G LRRK2 mutant MEF cells ± MLi-2 (200 nM) or conduritol β-epoxide (CBE) (300 µM). Long (B) and short (C) chase time points shown as fold change relative to WT control MEF cells time 0. Only BMP isoforms that were detected are shown. Data from 3 replicated experiments (mean ± SEM).
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Figure 4—source data 1
Plotted values in panels B, C.
- https://cdn.elifesciences.org/articles/106330/elife-106330-fig4-data1-v1.xlsx
Figure 5
LRRK2 activity modulates CLN5 expression levels.
(A) Whole cell lysates (WCL) from wild-type (WT) and R1441G LRRK2 mouse embryonic fibroblast (MEF) cells were analyzed by immunoblotting. Representative immunoblots of CLN5, phospho-Rab10 (pRab10), and α-Tubulin are shown from two (#1 and #2) out of six independent experiments. Molecular weight marker mobility is shown in kDa. Plot at the bottom shows quantification of CLN5 immunoblot levels (relative to WT). (B) WCL from R1441G LRRK2 MEF cells treated with 200 nM MLi-2 for 16 hr were analyzed by immunoblotting. Representative immunoblots of phospho-LRRK2 (pLRRK2), CLN5, and α-Tubulin levels are shown from two (#1 and #2) out of three independent experiments. Molecular weight marker mobility is shown in kDa. Plot at the bottom shows quantification of CLN5 immunoblot levels in WCL of R1441G LRRK2 MEF cells, untreated (ctrl) or treated with MLi-2. (C) WCL from G2019S LRRK2 patient-derived fibroblasts treated with indicated increasing MLi-2 concentrations for 16 hr were analyzed by immunoblotting. Immunoblots of CLN5, phospho-Rab10 (pRab10), and α-Tubulin levels are shown from one representative experiment (n = 6 per condition, obtained from two independent replicate experiments using fibroblast cell lines derived from three different patients). Molecular weight marker mobility is shown in kDa. Plot at the bottom shows quantification of CLN5 immunoblot levels relative to G2019S LRRK2 patient-derived fibroblasts treated with MLi-2 at the indicated concentrations. (D) WCL from R1441G LRRK2 patient-derived fibroblasts treated with indicated increasing MLi-2 concentrations for 24 hr were analyzed by immunoblotting. Immunoblots of CLN5, phospho-Rab10 (pRab10), and α-Tubulin levels are shown from one representative experiment. Significance in (A) and (B) determined by two-tailed, unpaired t-test; significance in (C) determined by Dunnett’s one-way ANOVA test; *p < 0.05, ***p < 0.001.
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Figure 5—source data 1
Uncropped blots.
- https://cdn.elifesciences.org/articles/106330/elife-106330-fig5-data1-v1.zip
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Figure 5—source data 2
Annotated uncropped blots.
- https://cdn.elifesciences.org/articles/106330/elife-106330-fig5-data2-v1.zip
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Figure 5—source data 3
Plotted values in panels A–C.
- https://cdn.elifesciences.org/articles/106330/elife-106330-fig5-data3-v1.xlsx
Figure 6 with 1 supplement
Pharmacological modulation of extracellular vesicle (EV)-mediated BMP exocytosis.
(A) Whole cell lysates (WCL) and isolated EVs from wild-type (WT) mouse embryonic fibroblast (MEF) cells treated with 10 µM GW4869 or 10 nM bafilomycin-A1 (B-A1) for 24 hr were analyzed by immunoblotting. Representative immunoblots of LAMP2, Flotillin-1, and α-Tubulin are shown. Molecular weight marker mobility is shown in kDa. Ultra-performance liquid chromatography–tandem mass spectrometry (UPLC–MS/MS) determination of EV-associated di-18:1-BMP normalized to protein content from WT MEF cells treated with 10 µM GW4869 (B) or 10 nM B-A1 (C) for 24 hr. Data shown as fold change relative to WT control MEF cells. Only BMP isoforms that were detected are shown. Data from 6 independent experiments (mean ± SEM). Significance determined by two-tailed unpaired t-test; *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001. Quantitation of BMP isoforms normalized to protein content in WCL from MEF WT cells treated with 10 µM GW4869 (D) or 10 nM B-A1 (E) for 24 hr. Data shown as fold change relative to WT control MEF cells. Only BMP isoforms that were detected are shown. Data from 3 independent experiments (mean ± SEM). Significance determined by two-tailed unpaired t-test; *p < 0.05, **p < 0.01, ***p < 0.001.
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Figure 6—source data 1
Uncropped blots.
- https://cdn.elifesciences.org/articles/106330/elife-106330-fig6-data1-v1.zip
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Figure 6—source data 2
Annotated uncropped blots.
- https://cdn.elifesciences.org/articles/106330/elife-106330-fig6-data2-v1.zip
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Figure 6—source data 3
Plotted values in panels B–E.
- https://cdn.elifesciences.org/articles/106330/elife-106330-fig6-data3-v1.xlsx
Figure 6—figure supplement 1
Pharmacological modulation of extracellular vesicle (EV)-mediated BMP exocytosis in mutant LRRK2 mouse embryonic fibroblast (MEF) cells.
Whole cell lysates (WCL) and isolated EVs from R1441G LRRK2 MEF cells treated with 10 µM GW4869 or 10 nM bafilomycin-A1 for 24 h were analyzed by immunoblotting. Representative images of LAMP2, Flotillin-1, and α-Tubulin levels are shown. Molecular weight marker mobility is shown in kDa.
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Figure 6—figure supplement 1—source data 1
Uncropped blots.
- https://cdn.elifesciences.org/articles/106330/elife-106330-fig6-figsupp1-data1-v1.zip
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Figure 6—figure supplement 1—source data 2
Annotated uncropped blots.
- https://cdn.elifesciences.org/articles/106330/elife-106330-fig6-figsupp1-data2-v1.zip
Figure 7 with 1 supplement
Patient-derived G2019S LRRK2 fibroblasts exhibit alterations of antibody-accessible BMP and increased endolysosomal exocytosis.
(A) Confocal microscopy of endogenous BMP (yellow) and LAMP1 (magenta) immunofluorescence in control (CTRL) and LRRK2-G2019S mutant-derived fibroblasts. Scale bar: 40 µm. Quantification of vesicular BMP intensity (B) and LAMP1 relative intensity (C) per cell area. Colored dots represent the mean value of three independent experiments (n = 3 CTRL and n = 3 G2019S LRRK2 fibroblast cell lines); violin plots show the distribution of individual cell data (60 cells per independent experiment). Significance determined by two-tailed paired t-test; ****p < 0.0001; ns, not significant. (D) Confocal microscopy of endogenous BMP (yellow) and CD63 (magenta) immunofluorescence in CTRL and G2019S LRRK2 fibroblasts. Scale bar: 10 µm. Quantification of the number of CD63 vesicles in the peripheral cell region (E) and the percentage of peripheral CD63 vesicles positive for BMP (F). Colored dots represent mean values of three independent experiments (n = 3 CTRL and n = 3 G2019S LRRK2 fibroblast cell lines); violin plots show the distribution of individual cell data (60 cells per independent experiment). Significance determined by two-tailed paired t-test; **p < 0.01; ns, not significant. (G) A representative confocal microscopy image of endogenous BMP (yellow) and transduced CD63-pHluorin (magenta) in a CTRL human fibroblast cell line used for total internal reflection fluorescence (TIRF) microscopy experiments. Inset image shows co-localization between BMP and CD63-pHluorin in vesicular structures (a similar degree of co-localization was observed in G2019S LRRK2 cells; data not shown). Scale bar: 10 µm. (H) Representative epifluorescence (EPI) and TIRF microscopy images of the same cell from a G2019S LRRK2 patient-derived fibroblast cell line treated with vehicle (DMSO) overnight. Inset images show a TIRF microscopy time-lapse sequence (0.3 s per frame) from a single CD63-pHluorin-positive fusion event at the plasma membrane. Scale bar: 10 µm. (I) Quantification of CD63-pHluorin-positive fusion events in stably expressing control (CTRL) and G2019S LRRK2 fibroblasts treated with vehicle (Ø) or 200 nM MLi-2 for 16 hr. Each dot represents one cell (n = 20 cells quantified from four CTRL and four G2019S LRRK2 cell lines). Significance determined by Tukey’s multiple comparisons test, ordinary one-way ANOVA; *p < 0.05, **p < 0.001.
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Figure 7—source data 1
IF images in panel A.
- https://cdn.elifesciences.org/articles/106330/elife-106330-fig7-data1-v1.zip
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Figure 7—source data 2
IF images in panel D.
- https://cdn.elifesciences.org/articles/106330/elife-106330-fig7-data2-v1.zip
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Figure 7—source data 3
IF images in panel G.
- https://cdn.elifesciences.org/articles/106330/elife-106330-fig7-data3-v1.zip
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Figure 7—source data 4
EPI and TIRF images in panel H.
- https://cdn.elifesciences.org/articles/106330/elife-106330-fig7-data4-v1.zip
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Figure 7—source data 5
Plotted values in panels B, C, E, F, I.
- https://cdn.elifesciences.org/articles/106330/elife-106330-fig7-data5-v1.xlsx
Figure 7—figure supplement 1
Analysis of endolysosomal fractions in control and G2019S LRRK2 human-derived skin fibroblasts.
(A) Immunoblots showing fractions recovered after ultracentrifugation of sucrose gradients of cell extracts from control (CTRL) and G2019S LRRK2 mutant-derived fibroblasts. Endolysosome fractions correspond to fractions 8–10. Representative immunoblots for LRRK2, CLN5, CD63, and α-Tubulin are shown. Plots on the right show quantification of LRRK2 and CLN5 band intensities. n = 3 CTRL and n = 3 G2019S LRRK2 fibroblast cell lines. Molecular weight marker mobility is shown in kDa. (B) Whole cell lysates from CTRL individuals and G2019S LRRK2 mutant-derived fibroblasts analyzed by immunoblotting. Representative blots of CD63 and Calnexin are shown. The plot on the right shows quantification of relative CD63 protein levels in whole cell lysates normalized to Calnexin (used as a loading control). Molecular weight marker mobility is shown in kDa. Significance determined by ordinary two-tailed paired t-test; ns, not significant.
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Figure 7—figure supplement 1—source data 1
Uncropped blots.
- https://cdn.elifesciences.org/articles/106330/elife-106330-fig7-figsupp1-data1-v1.zip
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Figure 7—figure supplement 1—source data 2
Annotated uncropped blots.
- https://cdn.elifesciences.org/articles/106330/elife-106330-fig7-figsupp1-data2-v1.zip
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Figure 7—figure supplement 1—source data 3
Plotted values in panels B, C, E, F, I.
- https://cdn.elifesciences.org/articles/106330/elife-106330-fig7-figsupp1-data3-v1.xlsx
Videos
Video 1
Time-lapse of vehicle (DMSO)-treated human G2019S LRRK2 fibroblast cell stably expressing CD63-pHluorin.
The timestamp on the upper left corner indicates seconds. Fusion events are indicated by white circles. Scale bar: 10 µm. Images were acquired at ~3.33 frames/s.
Video 2
Time-lapse of MLi-2-treated human G2019S LRRK2 fibroblast cell stably expressing CD63-pHluorin.
Cells were treated with 200 nM MLi-2 for 16 hr prior to analysis. The timestamp on the upper left corner indicates seconds. Fusion events are indicated by white circles. Scale bar: 10 µm. Images were acquired at ~3.33 frames/s.
Tables
Key resources table
| Reagent type (species) or resource | Designation | Source or reference | Identifiers | Additional information |
|---|---|---|---|---|
| Cell line (Mus musculus) | WT and R1441G LRRK2 MEFs | https://mrcppureagents.dundee.ac.uk/ | ||
| Cell line (Homo sapiens) | Control and G2019S LRRK2 fibroblasts | Fernández-Santiago et al., 2021 | ||
| Recombinant DNA reagent | CD63-pHluorin | Lu et al., 2018 | ||
| Antibody | anti-mouse LAMP2, clone GL2A7 (Rat monoclonal) | Developmental Studies Hybridoma Bank | GL2A7; RRID:AB_2281134 | IF (1:500) WB (1:1000) |
| Antibody | anti-Flotillin-1 (mouse monoclonal) | BD Biosciences | 610821; RRID:AB_398140 | WB (1:1000) |
| Antibody | anti-phospho-Rab10 (phospho T73) (Rabbit monoclonal) | Abcam | ab230261; RRID:AB_2811274 | WB (1:1000) |
| Antibody | Anti-alpha tubulin (mouse monoclonal) | Sigma-Aldrich | T5168; RRID:AB_477579 | WB (1:10000) |
| Antibody | anti-CLN5 (Rabbit monoclonal) | Abcam | ab170899; RRID:AB_3662651 | WB (1:1000) |
| Antibody | anti-phosphoLRRK2 (phosphor S935) (Rabbit monoclonal) | Abcam | ab133450; RRID:AB_2732035 | WB (1:1000) |
| Antibody | anti-LAMP1 XP D2D11 (Rabbit monoclonal) | Cell Signalling | 9091; RRID:AB_2687579 | IF (1:1000) |
| antibody | anti-CD63 [EPR22458-280] (Rabbit monoclonal) | Abcam | ab252919 | IF (1:500) WB (1:1000) |
| Antibody | anti-LRRK2 (Rabbit monoclonal) | Abcam | ab133474; RRID:AB_2713963 | WB (1:500) |
| Antibody | anti-calnexin (mouse monoclonal) | BD Transduction | 610523 | WB (1:1000) |
| Antibody | anti-GFP (Rabbit polyclonal) | Abcam | ab290; RRID:AB_303395 | WB (1:500) |
| Chemical compound, drug | MLi-2 | Tocris Bioscience | 5756 | 200 nM |
| Chemical compound, drug | Conduritol β-epoxide | MERCK | 234599 | 300 µM |
| Chemical compound, drug | Bafilomycin-A1 | Sigma-Aldrich | B1793 | 10 nM |
| Chemical compound, drug | GW4869 | SelleckChem | S7609 | 10 µM |
| Software, algorithm | FIJI | http://fiji.sc/ | SCR_002285 | |
| Software, algorithm | CellProfiler | https://cellprofiler.org/ | SCR_007358 |
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Extracellular vesicle-mediated release of bis(monoacylglycerol)phosphate is regulated by LRRK2 and glucocerebrosidase activity
eLife 14:RP106330.
https://doi.org/10.7554/eLife.106330.3
