Iovino L , Giusti V , Pischedda F , Giusto E , Plotegher N , Marte A , Battisti I , Di Iacovo A , Marku A , Piccoli G , Bandopadhyay R , Perego C , Bonifacino T , Bonanno G , Roseti C , Bossi E , Arrigoni G , Bubacco L , Greggio E , Hilfiker S , Civiero L .

GR-2016-02363461 Italian Ministry of Health

	Fig. 1. EAAT2 levels are decreased in human LRRK2 G2019S brains. a Western blot analysis of human LRRK2 G2019S caudate and putamen lysates and healthy controls using anti-EAAT2, anti-GS, and anti-GFAP antibodies; bd relative quantification of band intensity was performed using ImageJ and normalized to the housekeeping protein GAPDH (n=5 age-matched control samples and n=4 LRRK2 G2019S caudate and putamen samples); e representative double-labeling images for EAAT2 (green) and GFAP (red) in LRRK2 G2019S human caudate and putamen and age-matched control; scale bar 50 m, insets 20 m; f representative images of DAB-immunostaining for GFAP in LRRK2 G2019S human caudate and putamen and age-matched control; scale bar 25 m, insets 10 m; arrowheads in (e and f) indicate the presence of GFAP-positive cells. Statistical analysis in (b) was performed using MannWhitney test and in (c, d) using unpaired T test.
	Fig. 2. Glutamate transporter is downregulated in the striatum of LRRK2 G2019S mice. a Western blot analysis of LRRK2 WT and LRRK2 G2019S striatal lysates using anti-Glt-1, anti-GS, anti-GFAP, and anti-TH antibodies; be relative quantification of band intensity was performed using ImageJ and normalized to -actin (n=7 striatal samples for both LRRK2 WT and LRRK2 G2019S 4-month-old mice); f representative confocal double-labeling images for Glt-1 (green) and GFAP (red) in LRRK2 WT and G2019S striatal slices; scale bar 50 m, insets 20 m; g quantification of GFAP IntDen and GFAP+ cells (h) in the dorsal striatum of LRRK2 WT and G2019S mice. Three different fields per animal were collected, n=3 animals for each genotype; i representative confocal images of the cellular distribution of the endogenous Glt-1 (green) in primary striatal astrocytes stained for GFAP (cyan) derived from LRRK2 WT and LRRK2 G2019S mice treated with dbcAMP (500 M) for 10 days; scale bars 20 m, inserts 5 m; j striatal gliosomes from LRRK2 WT and LRRK2 G2019S 4-month-old mice were exposed for 2 min at 37 C to increasing concentration of [3H]D-Asp (0.03, 0.1, 1, 3, 30, and 100 M) in the presence of 10 M UCPH to exclude [3H]D-Asp uptake by Glast. The specific [3H]D-Asp uptake is expressed as nmol/mg protein/2 min; the kinetic parameters Vmax and Km were obtained by fitting data with the MichaelisMenten equation (n=4 independent experiments for each group). Statistical analysis in (b, e, h, and j) was performed using unpaired T test; statistical analysis in g was performed using MannWhitney test.
	Fig. 3. LRRK2 G2019S alters EAAT2 electrophysiological properties. a Schematic outline of the experimental setup. Oocytes were co-injected with mRNA of EAAT2 and human LRRK2 (WT or G2019S) and glutamate transport-associated currents were recorded using the two-electrode voltage-clamp technique; b the bar graph represents current amplitudes elicited in oocytes co-expressing EAAT2 and LRRK2 WT (n=79 oocytes, 12 frogs) or G2019S (n=122 oocytes, 12 frogs). Glutamate application was at 1 mM and the holding potential at60 mV; c transport-associated currents in oocytes co-expressing EAAT2 and LRRK2 WT or G2019S as a function of glutamate concentration. The kinetic parameters Imax and aKm were obtained by fitting data with the MichaelisMenten equation (n=6 oocytes; 2 frogs); d representative bright-field (left column) or fluorescence (middle column, merge on the right column) images of oocyte slices co-expressing EAAT2 (green) and LRRK2 WT or G2019S, with or without 90 min MLi-2 (200 nM) treatment; scale bar 20 m. Representative traces of the recorded transport current in all the three groups are shown on the right; e quantitative analysis of the IntDen of the EAAT2 signal at the oocyte membrane was performed in three different fields for each oocyte; n=3 oocytes for each group; f the bar graph represents current amplitudes elicited in oocytes co-expressing EAAT2 and LRRK2 WT (n=18 oocytes, 6 frogs), G2019S (n=22 oocytes, 6 frogs), or G2019S+MLi-2 (n=22 oocytes, 6 frogs). Statistical analysis in b was performed using MannWhitney test, in e using one-way ANOVA test (F=8.891, P=0.001) followed by Tukeys multiple comparison test. Statistical analysis in (f) was performed using unpaired T test to compare EAAT2+LRRK2 WT to EAAT2+G2019S-injected oocytes and with paired T test to compare EAAT2+G2019S oocytes before and after LRRK2 inhibition.
	Fig. 4. [panels a,b,c] Astroglial Glt-1 is mislocalized in the presence of LRRK2 G2019S mutation. a Representative TIRFM images of Glt-1 localization in LRRK2 WT and LRRK2 G2019S astrocytes (untreated or treated with MLi-2) transfected with GFP-Glt1 (gray) and stained with GFAP (cyan). Scale bar 20 m; insets 10 m; b) quantification of the GFP-Glt-1 mean fluorescence performed in TIRFM images (n=25 cells from LRRK2 WT, n=16 cells from LRRK2 WT+MLi-2; n=30 cells from LRRK2 GS and n=31 cells from LRRK2 GS+MLi-2, experiments performed at least in triple); c schematic representation of TPA and Go 6976 effects on PKC activity;
	Fig. 4. [panels d, e, f, g) Astroglial Glt-1 is mislocalized in the presence of LRRK2 G2019S mutation. [continued] d representative epifluorescence images of Glt-1 intracellular clusters in LRRK2 WT and LRRK2 G2019S astrocytes transfected with Flag-Glt-1 (green) and stained with GFAP (cyan) under basal condition and after pharmacological treatment; Scale bar 20 m, insets 5 m; e quantification of the number of Glt-1-positive clusters per cell in LRRK2 WT and G2019S astrocytes under basal condition and after pharmacological treatment using LRRK2 inhibitor MLi-2 (90 min) and the PKC activator TPA (20 min). Number of cells analyzed: LRRK2 WT (n=40 cells), LRRK2 WT+MLi-2 (n=13 cells), LRRK2 G2019S (n=31 cells), LRRK2 G2019S+MLi-2 (n=26 cells), LRRK2 WT+TPA (n=29 cells), and LRRK2 G2019S+TPA (n=18 cells); f quantification of the number of Glt-1-positive clusters per cell under basal condition and after pharmacological co-treatment with TPA and Mli-2 in LRRK2 WT astrocytes. Number of cells analyzed: LRRK2 WT (n=9 cells) and WT+TPA+MLI-2 (n=15 cells); g quantification of the number of Glt-1-positive clusters per cell under basal condition and after pharmacological treatment with the PKC inhibitor Go 6976 in LRRK2 G2019S astrocytes. Number cells analyzed: LRRK2 GS (n=11 cells) and LRRK2 GS+Go (n=12 cells). Experiments performed at least in triple. Three cells were analyzed for each independent cell culture. Statistical analysis in (b and e) was performed using two-way ANOVA (b treatment F=0.06 and p=0.06; genotypes F=53.01 and p<0.0001; e treatment: F=16.53 and p<0.0001; genotypes F=10.67 and p=0.001) test followed by Tukeys multiple comparisons test. ($ vs LRRK2 WT and * versus LRRK2 G2019S). Statistical analysis in (f and g) was performed using unpaired T test.
	Fig. 5. [panels a-g] LRRK2 G2019S enhances Glt-1 accumulation in Rab4-positive organelles. a Representative z-stack confocal images of primary astrocytes from LRRK2 WT and LRRK2 G2019S mice transfected with Flag-Glt-1 and GFP-Lamp1, GFP-Rab11, or GFP-Rab4 under basal conditions or upon treatment with MLi-2 inhibitor. Insets show Lamp1-, Rab11-, or Rab4-positive area and the localization of Glt-1 in the indicated ROIs. Scale bars: 20 m; insets 5 m; b, c quantitative analysis of Lamp1 IntDen (n=14 cells for LRRK2 WT, n=11 cells for LRRK2 GS and n=7 cells for LRRK2 GS+MLi2, experiments performed at least in triple) and of the Pearsons correlation coefficient of Glt-1 co-localizing with the Lamp1-positive compartment (n=14 cells for LRRK2 WT, n=12 cells for LRRK2 GS and n=8 cells for LRRK2 GS+MLi2, experiments performed at least in triple); de quantitative analysis of Rab11 IntDen (n=12 cells for LRRK2 WT, n=10 cells for LRRK2 GS and n=9 cells for LRRK2 GS+MLi2, experiments performed at least in triple) and of the Pearsons correlation coefficient of Glt-1 co-localizing with the Rab11-positive compartment (n=12 cells for LRRK2 WT, n=12 cells for LRRK2 GS and n=10 cells for LRRK2 GS+MLi2, experiments performed at least in triple); f, g Quantitative analysis of Rab4 IntDen (n=11 cells for LRRK2 WT, n=9 cells for LRRK2 GS and n=9 cells for LRRK2 GS+MLi2, experiments performed at least in triple) and of the Pearsons correlation coefficient of Glt-1 co-localizing with the Rab4-positive vesicles (n=13 cells for LRRK2 WT, n=13 cells for LRRK2 GS and n=9 cells for LRRK2 GS+MLi2, experiments performed at least in triple).
	Fig. 5. [panels h-l]. LRRK2 G2019S enhances Glt-1 accumulation in Rab4-positive organelles. h Representative TEM images of LRRK2 WT and G2019S endosomal-like structures (yellow arrowheads) in primary striatal astrocytes transfected with GFP-Rab4 and Flag-Glt-1 (scale bars: 5 m; insets: scale bars: 500 nm); i Quantification of the area of endosomal-like structures (n=5 cells analyzed for each group, ten independent fields were analyzed for quantification). jl Representative z-stack confocal images of coronal organotypic LRRK2 WT, LRRK2 G2019S, and LRRK2 G2019S treated with MLi-2 slices transfected with the GFP-Rab4 plasmid and stained for the endogenous proteins Glt-1 (red) and GFAP (magenta). Insets show Rab4-positive area and the localization of Glt-1 in the indicated ROIs. Scale bars: 20 m; insets 2 m; Statistical analysis in b-g was performed using one-way ANOVA test (b) F=3.77 and p=0.04; c F=0.36 and p=0.69, d F=0.53 and p=0.59, e F=2.77 and p=0.08, f F=1.76 and p=0.19, and g F=19.04 and p<0.0001) followed by Tukeys multiple comparison test. Statistical analysis in i was performed using unpaired t tests.
	Fig. 6. LRRK2 G2019S mutation enhances Rab4-positive organelles dimension via Rab8A and Rab10 phosphorylation. a Western blot analysis of extracts from primary striatal astrocyte cultures from LRRK2 WT, LRRK2 G2019S mice with or without MLi-2 treatment, and blotted with the following antibodies: anti-pS1292 LRRK2, anti-pS935 LRRK2, anti-total LRRK2, anti-p73T Rab10, anti-total Rab10, anti-p72T Rab8A, and anti-total Rab8A antibodies; b, d Representative z-stack confocal images of primary astrocytes from LRRK2 WT and LRRK2 G2019S mice transfected with GFP-Rab4 and Rab8A WT/QL or Rab10 WT/QL. Insets show the area of the Rab4-positive structures. Scale bars: 20 m; insets 1 m; c, e Quantification of Rab4-positive vesicle area in primary astrocytes from LRRK2 WT and LRRK2 G2019S mice transfected with GFP-Rab4 and Rab8A WT/QL or Rab10 WT/QL; at least n=6 cells have been analyzed for each experimental group and the experiments have been performed in triple. Statistical analysis in c was performed using the one-way ANOVA test (F=17.58 and p<0.0001) followed by Tukeys multiple comparisons test; Statistical analysis in e was performed using KruskalWallis test (p=0.0006) followed by Dunns multiple comparisons test.
	Fig. 7. [a-d] G2019S pathogenic LRRK2 mutation impacts on Glt-1 recycling and turnover. a Representative confocal images of primary striatal LRRK2 WT and G2019S astrocytes under basal conditions and treated with the recycling blocker Monensin (35 M, 40 min). Insets show the Rab4-positive area and the localization of Glt-1 in the indicated ROIs. Scale bars: 20 m; insets 5 m; b quantitative analysis of the Pearsons correlation coefficient of Glt-1 co-localizing with the Rab4-positive compartment; n=8 cells for LRRK2 WT, n=13 cells for LRRK2 WT+Monensin, n=9 cells for LRRK2 G2019S and n=12 cells for LRRK2 G2019S+Monensin, experiments performed at least in triple; c Representative z-stack confocal images of primary LRRK2 WT and G2019S (with or without MLi-2) striatal astrocytes transfected with Flag-Glt-1 (red) and GFP-Rab4 (green). The insets show Rab4-positive area and the localization of Glt-1 in these ROIs; scale bar 20 m; insets 5 m; d quantitative analysis of the Pearsons correlation coefficient of Glt-1 co-localizing with the Rab4-positive compartment in the four selected experimental time points. At least n=6 cells have been analyzed for each experimental group and the experiments have been performed in triple;
	Fig. 7. [e-i] G2019S pathogenic LRRK2 mutation impacts on Glt-1 recycling and turnover. e representative z-stack confocal images of primary striatal LRRK2 G2019S astrocytes transfected with GFP-Rab4 and Flag-Glt-1 (red) and labeled for endogenous Lamp1 (far red, pseudocolored in blue). Insets show Rab4- and Lamp1-positive area and the localization of Glt-1 in these ROIs. Scale bar 20 m; insets 5 m; f Quantitative analysis of the Pearsons correlation coefficient of Glt-1 co-localizing with the Rab4-positive vesicles in LRRK2 G2019S astrocytes under basal conditions (n=15 cells) or upon MG132 (n=15 cells) or Bafilomycin application (n=13 cells); g quantitative analysis of the Pearsons Correlation Coefficient of Glt-1 co-localizing with the Lamp1-positive structures in LRRK2 G2019S astrocytes under basal conditions (n=15 cells) or upon MG132 (n=15 cells) or Bafilomycin (n=13 cells) application; experiments performed at least in triple; h Quantitative analysis of Glt-1 IntDen in LRRK2 G2019S astrocytes, under basal condition or after application of MG132 or Bafilomycin A1 (n=15 cells for untreated LRRK2 GS, n=16 cells for LRRK2 GS+MG132 and n=13 LRRK2 GS+Bafilomycin; experiments performed at least in triple); i schematic representation of Glt-1 trafficking in LRRK2 WT and LRRK2 G2019S astrocytes. Statistical analysis in b was performed using two-way ANOVA test (treatment: F=12.86 and p=0.0009; Genotypes F=4.672 and p=0.03) followed by Tukeys multiple comparisons test; statistical analysis in d was performed using two-way ANOVA test (treatment: F=16.17 and p<0.0001; group: F=13.87 and p<0.0001) followed by Tukeys multiple comparison test; statistical analysis in (fh) was performed using one-way ANOVA test (f F=6.68 and p=0.003); g F=12.07 and p<0.0001; h F=5.79 and p=0.006) followed by Tukeys multiple comparisons test (*LRRK2 WT vs LRRK2 G2019S, #LRRK2 G2019S vs LRRK2 G2019S+MLi-2)

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