Inhibition of retrograde transport modulates misfolded protein accumulation and clearance in motoneuron diseases

Riccardo Cristofani, Valeria Crippa, Paola Rusmini, Maria Elena Cicardi, Marco Meroni, Nausicaa V Licata, Gessica Sala, Elisa Giorgetti, Christopher Grunseich, Mariarita Galbiati, Margherita Piccolella, Elio Messi, Carlo Ferrarese, Serena Carra, Angelo Poletti, Riccardo Cristofani, Valeria Crippa, Paola Rusmini, Maria Elena Cicardi, Marco Meroni, Nausicaa V Licata, Gessica Sala, Elisa Giorgetti, Christopher Grunseich, Mariarita Galbiati, Margherita Piccolella, Elio Messi, Carlo Ferrarese, Serena Carra, Angelo Poletti

Abstract

Motoneuron diseases, like spinal bulbar muscular atrophy (SBMA) and amyotrophic lateral sclerosis (ALS), are associated with proteins that because of gene mutation or peculiar structures, acquire aberrant (misfolded) conformations toxic to cells. To prevent misfolded protein toxicity, cells activate a protein quality control (PQC) system composed of chaperones and degradative pathways (proteasome and autophagy). Inefficient activation of the PQC system results in misfolded protein accumulation that ultimately leads to neuronal cell death, while efficient macroautophagy/autophagy-mediated degradation of aggregating proteins is beneficial. The latter relies on an active retrograde transport, mediated by dynein and specific chaperones, such as the HSPB8-BAG3-HSPA8 complex. Here, using cellular models expressing aggregate-prone proteins involved in SBMA and ALS, we demonstrate that inhibition of dynein-mediated retrograde transport, which impairs the targeting to autophagy of misfolded species, does not increase their aggregation. Rather, dynein inhibition correlates with a reduced accumulation and an increased clearance of mutant ARpolyQ, SOD1, truncated TARDBP/TDP-43 and expanded polyGP C9ORF72 products. The enhanced misfolded protein clearance is mediated by the proteasome, rather than by autophagy and correlates with the upregulation of the HSPA8 cochaperone BAG1. In line, overexpression of BAG1 increases the proteasome-mediated clearance of these misfolded proteins. Our data suggest that when the misfolded proteins cannot be efficiently transported toward the perinuclear region of the cells, where they are either degraded by autophagy or stored into the aggresome, the cells activate a compensatory mechanism that relies on the induction of BAG1 to target the HSPA8-bound cargo to the proteasome in a dynein-independent manner.

Keywords: BAG1; BAG3; HSPB8; aggregation; amyotrophic lateral sclerosis; autophagy; misfolded protein; proteasome; protein quality control.

Figures

Figure 1.
Figure 1.
Autophagic clearance of ARpolyQ. NSC34 cells cotransfected with AR.Q46 and pCDNA3 or HSPB8, and treated with vehicle (ethanol, EtOH) or 10 nM T, for 48 h. (A) Immunofluorescence microscopy (IF) analysis (63x magnification) of AR (green); nuclei were stained with DAPI (blue); scale bar: 20 μm. (B) WB and FRA show AR.Q46 total levels and AR.Q46 insoluble fraction respectively. TUBA was used as loading control. Bar graph represents the FRA mean relative optical density computed over 3 independent biological samples for each condition (n = 3) ± SD (* = P < 0.05, *** = P < 0.001; Two-Way ANOVA followed by the Uncorrected Fisher LSD test). (C) Phase contrast imaging and IF performed on NSC34 cells transfected with Dync1h1 siRNA show cell morphology and dynein distribution. Scale bar: 20 μm. (D) WB analysis of NSC34 cells transfected with Dync1h1 siRNA shows the levels of dynein heavy chain; TUBA was used as loading control. Bar graph represents the WB mean relative optical density measured over 3 independent biological samples for each condition (n = 3) ± SD (** = P<0.01, one-tailed unpaired Student t test). (E) FRA and WB of NSC34 stably expressing GFP-AR.Q39 and transfected with Dync1h1 siRNA show AR.Q39 insoluble fraction accumulation after 10 nM T treatment and reduction after dynein silencing. Bar graph represents the FRA mean relative optical density computed over 3 independent biological samples for each condition (n = 3) ± SD (* = P < 0.05, ** = P < 0.01; Two-Way ANOVA followed by the Uncorrected Fisher LSD test).
Figure 2.
Figure 2.
Effect of dynein-silencing on autophagy and ARpolyQ clearance. (A) Confocal microscopy analysis (40x magnification) performed on NSC34 cells transfected with Dync1h1 siRNA shows SQSTM1 or LC3 distribution (green); nuclei were stained with DAPI (blue); scale bars: 50 μm. Bar graphs represent the quantification of total green-fluorescence integrated density (IntDen) normalized on cells number. Six images were analyzed for each condition. (B) WB of LC3-I and LC3-II levels performed on NSC34 transfected with Dync1h1 siRNA and treated with 20 mM NH4Cl for the last 1.5 h. Nontargeting siRNA was used as control; TUBA was used as loading control. Bar graph represents the mean relative optical density computed over 3 independent biological samples for each condition (n = 3) ± SD (* = P < 0.05, ** = P < 0.01; Two-Way ANOVA followed by the Uncorrected Fisher LSD test); (C) WB of LC3-I and LC3-II levels performed on NSC34 treated with 100 μM EHNA and/or 20 mM NH4Cl for the last 1.5 h. Nontargeting siRNA was used as control; TUBA was used as loading control. Bar graphs represent the mean relative optical density computed over 3 independent biological samples for each condition (n = 3) ± SD (* = P < 0.05, ** = P < 0.01; Two-Way ANOVA followed by the Uncorrected Fisher LSD test).
Figure 3.
Figure 3.
Autophagy modulation by EHNA treatment. NSC34 cells treated with DMSO, 100 μM EHNA and/or 100 mM trehalose for 48 h; (A, B) the bar graph represents Sqstm1 and Lc3 mRNA relative levels normalized with Rplp0 mRNA levels. Analysis was conducted on 4 independent biological samples for each condition (n = 4) ± SD (** = P<0.01, *** = P<0.001; Two-Way ANOVA followed by the Uncorrected Fisher LSD test). (C) Confocal microscopy analysis shows SQSTM1 and LC3 localization (40x magnification); scale bars: 50 μm. Bar graph represents the quantification of total green fluorescence integrated density (IntDen) normalized on cells number. Six images were analyzed for each condition (n = 6) ± SD (** = P < 0.01, ** = P < 0.001; one-tailed unpaired Student t test). Lower gain was used to acquire trehalose-treated cells (low sensitivity [L.S.]) compared to control (high sensitivity [H.S.]). (D) WB analysis shows SQSTM1 and LC3 levels; TUBA was used as loading control. Bar graphs represent the mean relative optical density computed over 3 independent biological samples for each condition (n = 3) ± SD of SQSTM1:TUBA (middle inset) and LC3-II:TUBA (low inset) ratio (* = P < 0.05, ** = P < 0.01, *** = P < 0.001; One-Way ANOVA followed by the Uncorrected Fisher LSD test).
Figure 4.
Figure 4.
Effect of dynein ATPase activity-inhibition on ARpolyQ clearance. FRA and WB show ARpolyQ total levels and ARpolyQ insoluble fraction, respectively, of: (A) PC12 cells stably transfected with AR.Q10 and AR.Q112 induced with 1 μg/mL doxycycline for 72 h. Cells were treated with ethanol (EtOH) or 10 nM T and/or EHNA 100 μM for the last 48 h prior to analysis. TUBA was used as loading control and bar graphs represent the FRA mean relative optical density computed over 3 independent biological samples for each condition (n = 3) ± SD (*** = P<0.001; One-Way ANOVA followed by the Uncorrected Fisher LSD test); (B) TR4 NSC34 cells stably transfected with GFP-AR.Q0 induced with 1 μg/mL doxycycline for 72 h; (C) TR4 NSC34 cells stably transfected with GFP-AR.Q39 induced with 1 μg/mL doxycycline for 72 h; (D) NSC34 cells transiently transfected with AR.Q46 for 48 h. Cells were treated with ethanol (EtOH) or 10 nM T and/or EHNA 100 μM for the last 48 h prior to analysis. (C and D) TUBA was used as loading control and bar graphs represent the FRA mean relative optical density computed over 3 independent biological samples for each condition (n = 3) ± SD (* = P < 0.05, ** = P < 0.01; Two-Way ANOVA followed by the Uncorrected Fisher LSD test). (E) IF performed on NSC34 cells transfected with AR.Q46 and treated with 10 nM T or EtOH and 100 μM EHNA or DMSO for 48 h. AR was stained with AR H280 antibody (green), nuclei were stained with DAPI (blue) (63x magnification); scale bar: 20 μm. (F) Bar graph represents the mean percentage of transfected cells with inclusions computed over 3 independent biological samples for each condition (n = 3) ± SD (* = P < 0.05, *** = P < 0.001; Two-Way ANOVA followed by the Uncorrected Fisher LSD test). Ten fields for each biological sample were analyzed. (G) WB analysis of PBS, Triton X100, SDS and FA lysates fractions of NSC34 cells transfected with AR.Q46 and treated with 10 nM T or EtOH and 100 μM EHNA or DMSO for 48 h. GAPDH was used as loading control.
Figure 5.
Figure 5.
Dynein ATPase activity inhibition promotes ARpolyQ clearance via UPS. (A) NSC34 cells stably transfected with GFP-AR.Q39, treated with 10 nM T, 10 mM 3MA and/or 100 μM EHNA for the last 48 h and/or 10 μM MG132 for the last 16 h. WB shows ARpolyQ levels and FRA shows ARpolyQ insoluble fraction. Bar graph represents the FRA mean relative optical density computed over 3 independent biological samples for each condition (n = 3) ± SD (** = P < 0.01; *** = P < 0.001; one-tailed unpaired Student t test). (B) NSC34 cells transfected with GFPu reporter and/or ARpolyQ and treated with 10 nM T and/or 100 μM EHNA. WB shows ARpolyQ and GFPu bands; TUBA was used as loading control. Bar graph represents the GFP WB densitometric analysis of 3 independent samples for each condition (n = 3) ± SD (* = P < 0.05; *** = P < 0.001; Two-Way ANOVA followed by the Uncorrected Fisher LSD test); (C) Proteasome chymotryptic activity assay performed on NSC34 treated with DMSO or 100 μM EHNA and 10 μM MG132 used as negative control. Bar graph represents the mean relative fluorescence normalized on control group and computed over 4 independent biological samples for each condition (n = 4) ± SD (*** = P < 0.001, One-Way ANOVA followed by the Uncorrected Fisher LSD test). (D) Proteasome chymotryptic activity assay performed on NSC34 transfected with AR.Q46 and treated with 10 nM T, DMSO or 100 μM EHNA and 10 μM MG132 used as negative control. Bar graph represents the mean relative fluorescence normalized on control group and computed over 4 independent biological samples for each condition (n = 4) ± SD (*** = P < 0.001, One-Way ANOVA followed by the Uncorrected Fisher LSD test). (E) β-galactosidase assay performed on NSC34 cells transfected with pCMV-β and treated with DMSO or 100 μM EHNA for 24 or 48 h after transfection. Bar graph represents the mean relative absorbance normalized on transfected cells treated for 48 h and computed over 6 independent biological samples for each condition (n = 6) ± SD (Two-Way ANOVA, not significant). (F) MTT assay performed on NSC34 cells treated with DMSO or 100 μM EHNA for 24 or 48 h. Bar graph represents the mean relative absorbance normalized on untreated group and computed over 6 independent biological samples for each condition (n = 6) ± SD (One-Way ANOVA, not significant).
Figure 6.
Figure 6.
BAG1 upregulation reduces ARpolyQ accumulation. (A to C) NSC34 cells treated with DMSO or 100 μM EHNA for 48 h. The bar graphs represent Hspb8 (A), Bag3 (B) and Bag1 (C) mRNA levels normalized with Rplp0 mRNA levels. Four independent biological samples for each condition were analyzed (n = 4) ± SD (*** = P < 0.001; One-Way ANOVA followed by the Uncorrected Fisher LSD test). (D) NSC34 cells overexpressing AR.Q46 alone or coexpressing BAG1 and treated with T for last 48 h. FRA shows insoluble AR-polyQ levels (upper panel) and bar graph represents the FRA mean relative optical density computed over 3 independent biological samples for each condition (n = 3) ± SD (* = P < 0.05, *** = P < 0.001; Two-Way ANOVA followed by the Uncorrected Fisher LSD test). WB (lower panel) shows AR.Q46 and BAG1 protein levels. (E) NSC34 cells expressing AR.Q46 alone or coexpressing BAG1 and treated with 10 nM T for last 48 h and/or 10 μM MG132 for last 16 h. FRA shows insoluble AR-polyQ levels, bar graph represents the FRA mean relative optical density computed over 3 independent biological samples for each condition (n = 3) ± SD (* = P < 0.05, *** = P < 0.001; Two-Way ANOVA followed by the Uncorrected Fisher LSD test and one-tailed unpaired Student t test for control condition). (F) WB analysis of NSC34 cells transfected with Bag1 siRNA shows the levels of BAG1; TUBA was used as loading control. Bar graph represents the WB mean relative optical density computed over 3 independent biological samples for each condition (n = 3) ± SD (** = P < 0.01, one-tailed unpaired Student t test). (G) FRA and WB of NSC34 transfected with AR.Q46 and with Bag1 siRNA shows AR.Q46 insoluble fraction; TUBA was used as loading control. Bar graph represents the FRA densitometric analysis of 3 independent biological samples for each condition (n = 3) ± SD (** = P < 0.01; *** = P < 0.001; one-tailed unpaired Student t test).
Figure 7.
Figure 7.
EHNA effects on neuronal and motoneuronal cells obtained by differentiation of human iPSCs generated from SBMA patients. (A) IF analysis of neuronal and motoneuronal cells obtained by differentiation of human iPSCs generated from SBMA patients and treated with ethanol or 10 nM T (40x magnification). TUBB3 (green) and SMI312 (red) (upper inset), AR (green) and MNX1/HB9 (red) (lower inset). Nuclei were stained with DAPI (blue); scale bars: 30 μm. (B) Bar graph represents the percentage of MNX1/HB9-positive cells; 6 fields for each condition were analyzed (n = 6) ± SD (one-tailed unpaired Student t test, not significant). (C to I) RealTime PCR analyses performed on iPSCs differentiated to neuronal cells treated with 10 nM T and/or 100 μM EHNA for last 48 h. The bar graphs represent HSPB8 (C), BAG3 (D), BAG1 (E), SQSTM1 (F), LC3 (G), TFEB (H) and BECN1 (I) mRNA levels normalized with RPLP0 mRNA levels. Four independent samples for each condition were analyzed (n = 4) ± SD (* = P < 0.05, ** = P < 0.01, *** = P < 0.001; Two-Way ANOVA followed by the Uncorrected Fisher LSD test).
Figure 8.
Figure 8.
Effects of dynein inhibition on SOD1 and TARDBP insoluble species. (A) NSC34 cells expressing wtSOD1 and SOD1G93A treated with DMSO or 100 μM EHNA for last 48 h. FRA shows SOD1G93A accumulation compared to wtSOD1 and SOD1G93A reduction after 100 μM EHNA treatment. WB shows total level of transfected SOD1, TUBA was used as loading control. (B) NSC34 stably transfected with wtSOD1 or SOD1G93A induced with doxycycline and treated with DMSO or 100 μM EHNA for last 48 h. FRA shows SOD1G93A accumulation compared to wtSOD1 and SOD1G93A reduction after 100 μM EHNA treatment. WB shows total level of transfected SOD1, TUBA was used as loading control. (C) NSC34 expressing FL and TARDBPΔC treated with DMSO or 100 μM EHNA for last 48 h. FRA shows TARDBPΔC accumulation compared to FL TARDBP and TARDBPΔC reduction after 100 μM EHNA treatment. WB shows total level of transfected TARDBP, TUBA was used as loading control; (A to C) Bar graphs represent the FRA mean relative optical density computed over 3 independent biological samples for each condition (n = 3) ± SD (** = P < 0.01, *** = P < 0.001; Two-Way ANOVA followed by the Uncorrected Fisher LSD test). (D and E) NSC34 expressing SOD1G93A (D) or TARDBPΔC (E) and treated with DMSO, 100 μM EHNA and/or 10 mM 3MA for the last 48 h and 10 μM MG132 for the last 16 h. FRAs show SOD1G93A (D) or TARDBPΔC (E) accumulation after 3MA and MG132 treatments. EHNA treatment counteracts 3MA activity but not MG132 activity. WBs show total level of transfected SOD1 (D) or TARDBPΔC (E), TUBA or GAPDH was used as loading control. Bar graphs represent the FRA mean relative optical density computed over 3 independent biological samples for each condition (n = 3) ± SD (* = P < 0.05, ** = P < 0.01, *** = P < 0.001; Two-Way ANOVA followed by the Uncorrected Fisher LSD test and one-tailed unpaired Student t test for control conditions).
Figure 9.
Figure 9.
Effects of dynein inhibition on poly-GP insoluble fraction. (A) NSC34 cells expressing poly-GP (100 repeats) treated with 10 mM 3MA and/or 100 μM EHNA for the last 48 h prior to analysis and/or 10 μM MG132 for the last 16 h prior to analysis. FRA shows poly-GP insoluble fraction. Bar graphs represent the FRA mean relative optical density computed over 3 independent biological samples for each condition (n = 3) ± SD (** = P < 0.01; *** = P < 0.001; one-tailed unpaired Student t test); (B) the portion shown in A by the rectangle has been magnified to show the differences between short bars. WB shows total level of transfected poly-GP; TUBA was used as loading control.

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