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Metformin lowers Ser-129 phosphorylated α-synuclein levels via mTOR-dependent protein phosphatase 2A activation

Pérez-Revuelta, B I, Hettich, M M, Ciociaro, A, Rotermund, C, Kahle, P J, Krauss, S, Di Monte, D A·2014·Cell Death & Disease
DOI 10.1038/cddis.2014.175PMC PMC4047877
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Figure 1 Dose- and time-dependent effect of metformin on phospho-Ser129 α-syn levels in SH-SY5Y cells. SH-SY5Y cells with tetracycline-inducible expression of hα-syn were immunostained with an anti-β-III tubulin antibody, and representative images were taken before (a) and after (b) differentiation treatment with retinoic acid. Differentiated cultures were costained with Dapi (blue) and an anti-phospho-Ser129 α-syn antibody (green); representative images show cells before (c) and after (d) treatment with tetracycline. Scale bars=50 μm. Cells were differentiated with retinoic acid and incubated without or with tetracycline. After cell homogenization, levels of hα-syn (e) and phospho-Ser129 hα-syn (f) were assayed by western blotting in the supernatant and pellet fractions. Cells pretreated with retinoic acid and tetracycline were then incubated for 16 h in the absence or presence of metformin at different concentrations. Levels of hα-syn, phospho-Ser129 hα-syn and tubulin were assayed by immunoblotting in the supernatant fraction (g). Semiquantitative analysis of band intensities is expressed as hα-syn/tubulin ratio (h) or phospho-Ser129 hα-syn/hα-syn ratio (i). In separate experiments, differentiated cells pretreated with tetracycline were incubated in the presence of 2.5 mM metformin. Levels of hα-syn, phospho-Ser129 hα-syn and tubulin were assayed by western blotting at 0 h and after 16 and 24 h (j). Analysis of band intensities is expressed as phospho-Ser129 hα-syn / hα-syn ratio (k). Data in (h, i and k) are the means±S.E.M. of at least three independent experiments. *P<0.05, **P<0.01 and ***P<0.001 versus the respective control group (black bar). †††P<0.001 versus the group treated with 0.5 mM metformin (i). †P<0.05 versus the group treated with metformin for 16 h (k)
Figure 1 Dose- and time-dependent effect of metformin on phospho-Ser129 α-syn levels in SH-SY5Y cells. SH-SY5Y cells with tetracycline-inducible expression of hα-syn were immunostained with an anti-β-III tubulin antibody, and representative images were taken before (a) and after (b) differentiation treatment with retinoic acid. Differentiated cultures were costained with Dapi (blue) and an anti-phospho-Ser129 α-syn antibody (green); representative images show cells before (c) and after (d) treatment with tetracycline. Scale bars=50 μm. Cells were differentiated with retinoic acid and incubated without or with tetracycline. After cell homogenization, levels of hα-syn (e) and phospho-Ser129 hα-syn (f) were assayed by western blotting in the supernatant and pellet fractions. Cells pretreated with retinoic acid and tetracycline were then incubated for 16 h in the absence or presence of metformin at different concentrations. Levels of hα-syn, phospho-Ser129 hα-syn and tubulin were assayed by immunoblotting in the supernatant fraction (g). Semiquantitative analysis of band intensities is expressed as hα-syn/tubulin ratio (h) or phospho-Ser129 hα-syn/hα-syn ratio (i). In separate experiments, differentiated cells pretreated with tetracycline were incubated in the presence of 2.5 mM metformin. Levels of hα-syn, phospho-Ser129 hα-syn and tubulin were assayed by western blotting at 0 h and after 16 and 24 h (j). Analysis of band intensities is expressed as phospho-Ser129 hα-syn / hα-syn ratio (k). Data in (h, i and k) are the means±S.E.M. of at least three independent experiments. *P<0.05, **P<0.01 and ***P<0.001 versus the respective control group (black bar). †††P<0.001 versus the group treated with 0.5 mM metformin (i). †P<0.05 versus the group treated with metformin for 16 h (k)CC BY-NC-ND · PubMed Central
Figure 2 OKA, a PP2A inhibitor, prevents metformin-induced reduction of phospho-Ser129 α-syn. SH-SY5Y cells were pretreated with retinoic acid and tetracycline. Cells were then incubated for 16 h with no addition or in the presence of OKA alone (15 nM), metformin alone (2.5 mM) or both OKA and metformin. Levels of hα-syn, phospho-Ser129 hα-syn and tubulin were assayed by immunoblotting (a). Semiquantitative analysis of band intensities is expressed as phospho-Ser129 hα-syn/hα-syn ratio (b). In separate experiments, cells were treated with no addition or with 300 nM OKA for 4 h, and levels of hα-syn, phospho-Ser129 hα-syn and tubulin were assayed by western blotting (c, first two lanes). In cultures preincubated with OKA, the medium was removed, cells were washed with fresh medium and incubations were continued for 16 h in the absence or presence of 2.5 mM metformin. Levels of hα-syn, phospho-Ser129 hα-syn and tubulin were assayed by western blotting (c, third and fourth lanes). Analysis of band intensities is expressed as phospho-Ser129 hα-syn/hα-syn ratio (d). Data in (b and d) are the means±S.E.M. of at least three independent experiments. *P<0.05, **P<0.01 and ***P<0.001 versus the respective control group (black bar). †P<0.05 versus the group treated with OKA alone (b). ##P<0.01 versus the group treated with both OKA and metformin (b). †††P<0.001 versus the group pretreated with OKA for 4 h (d). #P<0.05 versus the group pretreated with OKA and then incubated in the absence of metformin (d)
Figure 2 OKA, a PP2A inhibitor, prevents metformin-induced reduction of phospho-Ser129 α-syn. SH-SY5Y cells were pretreated with retinoic acid and tetracycline. Cells were then incubated for 16 h with no addition or in the presence of OKA alone (15 nM), metformin alone (2.5 mM) or both OKA and metformin. Levels of hα-syn, phospho-Ser129 hα-syn and tubulin were assayed by immunoblotting (a). Semiquantitative analysis of band intensities is expressed as phospho-Ser129 hα-syn/hα-syn ratio (b). In separate experiments, cells were treated with no addition or with 300 nM OKA for 4 h, and levels of hα-syn, phospho-Ser129 hα-syn and tubulin were assayed by western blotting (c, first two lanes). In cultures preincubated with OKA, the medium was removed, cells were washed with fresh medium and incubations were continued for 16 h in the absence or presence of 2.5 mM metformin. Levels of hα-syn, phospho-Ser129 hα-syn and tubulin were assayed by western blotting (c, third and fourth lanes). Analysis of band intensities is expressed as phospho-Ser129 hα-syn/hα-syn ratio (d). Data in (b and d) are the means±S.E.M. of at least three independent experiments. *P<0.05, **P<0.01 and ***P<0.001 versus the respective control group (black bar). †P<0.05 versus the group treated with OKA alone (b). ##P<0.01 versus the group treated with both OKA and metformin (b). †††P<0.001 versus the group pretreated with OKA for 4 h (d). #P<0.05 versus the group pretreated with OKA and then incubated in the absence of metformin (d)CC BY-NC-ND · PubMed Central
Figure 3 Effects of metformin on AMPK- and mTOR-dependent phosphorylation. SH-SY5Y cells were pretreated with retinoic acid and tetracycline. Cells were then incubated for 16 h with no addition or in the presence of 2.5 mM metformin. Levels of ACC, p-ACC (the product of AMPK-dependent phosphorylation of ACC at Ser79) and tubulin were assayed by immunoblotting (a). Levels of RPS6, p-RPS6 (the product of mTOR-dependent phosphorylation of RPS6 at Ser240/244) and tubulin were measured by western blotting (c). Semiquantitative analysis of band intensities is expressed as p-ACC/ACC (b) or p-RPS6/RPS6 (d) ratios. Data in (b and d) are the means±S.E.M. of at least three independent experiments. *P<0.05 and **P<0.01 versus the respective control group (black bar)
Figure 3 Effects of metformin on AMPK- and mTOR-dependent phosphorylation. SH-SY5Y cells were pretreated with retinoic acid and tetracycline. Cells were then incubated for 16 h with no addition or in the presence of 2.5 mM metformin. Levels of ACC, p-ACC (the product of AMPK-dependent phosphorylation of ACC at Ser79) and tubulin were assayed by immunoblotting (a). Levels of RPS6, p-RPS6 (the product of mTOR-dependent phosphorylation of RPS6 at Ser240/244) and tubulin were measured by western blotting (c). Semiquantitative analysis of band intensities is expressed as p-ACC/ACC (b) or p-RPS6/RPS6 (d) ratios. Data in (b and d) are the means±S.E.M. of at least three independent experiments. *P<0.05 and **P<0.01 versus the respective control group (black bar)CC BY-NC-ND · PubMed Central
Figure 4 Levels of phospho-Ser129 α-syn are decreased by the mTOR inhibitor rapamycin. SH-SY5Y cells were pretreated with retinoic acid and tetracycline. Cells were then incubated for 16 h with no addition or in the presence of 2 μM rapamycin. Levels of RPS6, p-RPS6, hα-syn, phospho-Ser129 hα-syn and tubulin were assayed by immunoblotting (a). Semiquantitative analysis of band intensities is expressed as hα-syn/tubulin ratio (b) or phospho-Ser129 hα-syn/hα-syn ratio (c). In separate experiments, cells were incubated for 16 h with no addition or in the presence of OKA alone (15 nM), rapamycin alone (2 μM) or both OKA and rapamycin. Levels of hα-syn, phospho-Ser129 hα-syn and tubulin were assayed by immunoblotting (d). Semiquantitative analysis of band intensities is expressed as phospho-Ser129 hα-syn/hα-syn ratio (e). Data in (b, c and e) are the means±S.E.M. of at least three independent experiments. **P<0.01 and ***P<0.001 versus the respective control group (black bar). †††P<0.001 versus the group treated with OKA alone. ###P<0.001 versus the group treated with both OKA and rapamycin
Figure 4 Levels of phospho-Ser129 α-syn are decreased by the mTOR inhibitor rapamycin. SH-SY5Y cells were pretreated with retinoic acid and tetracycline. Cells were then incubated for 16 h with no addition or in the presence of 2 μM rapamycin. Levels of RPS6, p-RPS6, hα-syn, phospho-Ser129 hα-syn and tubulin were assayed by immunoblotting (a). Semiquantitative analysis of band intensities is expressed as hα-syn/tubulin ratio (b) or phospho-Ser129 hα-syn/hα-syn ratio (c). In separate experiments, cells were incubated for 16 h with no addition or in the presence of OKA alone (15 nM), rapamycin alone (2 μM) or both OKA and rapamycin. Levels of hα-syn, phospho-Ser129 hα-syn and tubulin were assayed by immunoblotting (d). Semiquantitative analysis of band intensities is expressed as phospho-Ser129 hα-syn/hα-syn ratio (e). Data in (b, c and e) are the means±S.E.M. of at least three independent experiments. **P<0.01 and ***P<0.001 versus the respective control group (black bar). †††P<0.001 versus the group treated with OKA alone. ###P<0.001 versus the group treated with both OKA and rapamycinCC BY-NC-ND · PubMed Central
Figure 5 Effects of metformin in HeLa cells. As compared with SHSY5Y cells, HeLa cells do not express LKB1, as indicated by the lack of LKB1 immunoreactivity by immunoblotting (a). Levels of ACC, p-ACC and tubulin were compared in HeLa cells incubated in the absence or presence of 2.5 mM metformin. Proteins were assayed by western blotting (b). Band intensities were quantified and expressed as p-ACC/ACC ratio (c). HeLa cells were transiently transfected with hα-syn and then incubated for 16 h in the absence or presence of metformin at different concentrations. Levels of hα-syn, phospho-Ser129 hα-syn and tubulin were assayed by immunoblotting (d). Semiquantitative analysis of band intensities is expressed as phospho-Ser129 hα-syn/hα-syn ratio (e). In separate experiments, hα-syn-expressing HeLa cells were incubated for 16 h with no addition or in the presence of OKA alone (20 nM), metformin alone (2.5 mM) or both OKA and metformin. Levels of hα-syn, phospho-Ser129 hα-syn and tubulin were assayed by immunoblotting (f). Semiquantitative analysis of band intensities is expressed as phospho-Ser129 hα-syn/hα-syn ratio (g). Levels of RPS6, p-RPS6 and tubulin were compared by western blot analysis in HeLa cells incubated in the absence or presence of metformin at different concentrations (h). Band intensities were quantified and expressed as p-RPS6/RPS6 ratio (i). Data in (c, e, g and i) are the means±S.E.M. of at least three independent experiments. *P<0.05, **P<0.01 and ***P<0.001 versus the respective control group (black bar). †P<0.05 versus the group treated with 0.5 mM metformin (e). †P<0.05 versus the group treated with OKA alone, and #P<0.05 versus the group treated with both OKA and metformin (g). †P<0.05 versus the group treated with 0.5 mM metformin, and #P<0.05 versus the group treated with 1 mM metformin (i)
Figure 5 Effects of metformin in HeLa cells. As compared with SHSY5Y cells, HeLa cells do not express LKB1, as indicated by the lack of LKB1 immunoreactivity by immunoblotting (a). Levels of ACC, p-ACC and tubulin were compared in HeLa cells incubated in the absence or presence of 2.5 mM metformin. Proteins were assayed by western blotting (b). Band intensities were quantified and expressed as p-ACC/ACC ratio (c). HeLa cells were transiently transfected with hα-syn and then incubated for 16 h in the absence or presence of metformin at different concentrations. Levels of hα-syn, phospho-Ser129 hα-syn and tubulin were assayed by immunoblotting (d). Semiquantitative analysis of band intensities is expressed as phospho-Ser129 hα-syn/hα-syn ratio (e). In separate experiments, hα-syn-expressing HeLa cells were incubated for 16 h with no addition or in the presence of OKA alone (20 nM), metformin alone (2.5 mM) or both OKA and metformin. Levels of hα-syn, phospho-Ser129 hα-syn and tubulin were assayed by immunoblotting (f). Semiquantitative analysis of band intensities is expressed as phospho-Ser129 hα-syn/hα-syn ratio (g). Levels of RPS6, p-RPS6 and tubulin were compared by western blot analysis in HeLa cells incubated in the absence or presence of metformin at different concentrations (h). Band intensities were quantified and expressed as p-RPS6/RPS6 ratio (i). Data in (c, e, g and i) are the means±S.E.M. of at least three independent experiments. *P<0.05, **P<0.01 and ***P<0.001 versus the respective control group (black bar). †P<0.05 versus the group treated with 0.5 mM metformin (e). †P<0.05 versus the group treated with OKA alone, and #P<0.05 versus the group treated with both OKA and metformin (g). †P<0.05 versus the group treated with 0.5 mM metformin, and #P<0.05 versus the group treated with 1 mM metformin (i)CC BY-NC-ND · PubMed Central
Figure 6 Effect of metformin on phospho-Ser129 α-syn levels in primary hippocampal neurons. Representative images of primary hippocampal neurons immunostained with antibodies against α-syn (a) and phospho-Ser129 α-syn (b). Colocalization is shown in the merged panel (c). Scale bar=100 μm. Primary hippocampal neurons were incubated for 24 h in the absence or presence of 5 μM metformin. Levels of α-syn, phospho-Ser129 α-syn and tubulin were assayed by immunoblotting (d). Semiquantitative analysis of band intensities is expressed as α-syn/tubulin ratio (e) or phospho-Ser129 α-syn/α-syn ratio (f). Data in (e and f) are the means±S.E.M. of at least three independent experiments. *P<0.05 versus the control group (black bar)
Figure 6 Effect of metformin on phospho-Ser129 α-syn levels in primary hippocampal neurons. Representative images of primary hippocampal neurons immunostained with antibodies against α-syn (a) and phospho-Ser129 α-syn (b). Colocalization is shown in the merged panel (c). Scale bar=100 μm. Primary hippocampal neurons were incubated for 24 h in the absence or presence of 5 μM metformin. Levels of α-syn, phospho-Ser129 α-syn and tubulin were assayed by immunoblotting (d). Semiquantitative analysis of band intensities is expressed as α-syn/tubulin ratio (e) or phospho-Ser129 α-syn/α-syn ratio (f). Data in (e and f) are the means±S.E.M. of at least three independent experiments. *P<0.05 versus the control group (black bar)CC BY-NC-ND · PubMed Central
Figure 7 Effect of metformin on phospho-Ser129 α-syn levels in the mouse brain. Mice received 5 g/kg metformin in the food pellet for 1 month (a, b and c) or 5 g/l metformin in the drinking water for 6 months (d, e and f). Levels of α-syn, phospho-Ser129 α-syn, tubulin and actin were assayed by immunoblotting of the brain homogenates (a and d). Semiquantitative analysis of band intensities is expressed as α-syn/tubulin ratio (b), α-syn/actin ratio (e) or phospho-Ser129 α-syn/α-syn ratio (c and f). Data in (b and c) are the means±S.E.M. of 20 mice/group. Data in (e and f) are the means±S.E.M. of four mice/group. **P<0.01 and ***P<0.001 versus the respective control group (black bar)
Figure 7 Effect of metformin on phospho-Ser129 α-syn levels in the mouse brain. Mice received 5 g/kg metformin in the food pellet for 1 month (a, b and c) or 5 g/l metformin in the drinking water for 6 months (d, e and f). Levels of α-syn, phospho-Ser129 α-syn, tubulin and actin were assayed by immunoblotting of the brain homogenates (a and d). Semiquantitative analysis of band intensities is expressed as α-syn/tubulin ratio (b), α-syn/actin ratio (e) or phospho-Ser129 α-syn/α-syn ratio (c and f). Data in (b and c) are the means±S.E.M. of 20 mice/group. Data in (e and f) are the means±S.E.M. of four mice/group. **P<0.01 and ***P<0.001 versus the respective control group (black bar)CC BY-NC-ND · PubMed Central

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Metadata

Authors
Pérez-Revuelta, B. I., Hettich, M. M., Ciociaro, A., Rotermund, C., Kahle, P. J., Krauss, S., & Di Monte, D. A.
Venue
Cell Death & Disease
Publisher
Springer Science and Business Media LLC
Published
2014-05-08
Volume
5
Issue
5
Pages
e1209-e1209
ISSN
2041-4889
DOI
10.1038/cddis.2014.175
PMC
PMC4047877
Cited by
140
References
6
Language
en
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