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Indole and synthetic derivative activate chaperone expression to reduce polyQ aggregation in SCA17 neuronal cell and slice culture models.

Kung PJ, Tao YC, Hsu HC, Chen WL, Lin TH, Janreddy D, Yao CF, Chang KH, Lin JY, Su MT, Wu CH, Lee-Chen GJ, Hsieh-Li HM - Drug Des Devel Ther (2014)

Bottom Line: The molecular chaperones act in preventing protein aggregation to ameliorate downstream harmful events.We found that indole and NC001-8 up-regulated chaperone expression to reduce polyQ aggregation in neuronal differentiated TBP/Q79 cells.Our results demonstrate how indole and derivative NC001-8 reduce polyQ aggregation to support their therapeutic potentials in SCA17 treatment.

View Article: PubMed Central - PubMed

Affiliation: Department of Life Science, National Taiwan Normal University, Taipei, Taiwan.

ABSTRACT
In spinocerebellar ataxia type 17 (SCA17), the expansion of a translated CAG repeat in the TATA box binding protein (TBP) gene results in a long polyglutamine (polyQ) tract in the TBP protein, leading to intracellular accumulation of aggregated TBP and cell death. The molecular chaperones act in preventing protein aggregation to ameliorate downstream harmful events. In this study, we used Tet-On SH-SY5Y cells with inducible SCA17 TBP/Q79-green fluorescent protein (GFP) expression to test indole and synthetic derivative NC001-8 for neuroprotection. We found that indole and NC001-8 up-regulated chaperone expression to reduce polyQ aggregation in neuronal differentiated TBP/Q79 cells. The effects on promoting neurite outgrowth and on reduction of aggregation on Purkinje cells were also confirmed with cerebellar primary and slice cultures of SCA17 transgenic mice. Our results demonstrate how indole and derivative NC001-8 reduce polyQ aggregation to support their therapeutic potentials in SCA17 treatment.

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Indole and derivative NC001-8 and cytotoxicity.Notes: (A) Structure, formula, and molecular weight of indole and synthetic derivative NC001-8. (B) Cytotoxicity of GGA, indole, and NC001-8 against SH-SY5Y cells, using Hoechst-propidium iodide staining. Cells were treated with 100 nM~100 μM tested compounds, and cell proliferation was measured the next day (n=3). The half maximal inhibitory concentration of each compound was shown under the columns. To normalize, the relative viability in untreated cells is set as 100%.Abbreviations: GGA, geranylgeranylacetone; IC50, inhibitory concentration at 50% level.
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f1-dddt-8-1929: Indole and derivative NC001-8 and cytotoxicity.Notes: (A) Structure, formula, and molecular weight of indole and synthetic derivative NC001-8. (B) Cytotoxicity of GGA, indole, and NC001-8 against SH-SY5Y cells, using Hoechst-propidium iodide staining. Cells were treated with 100 nM~100 μM tested compounds, and cell proliferation was measured the next day (n=3). The half maximal inhibitory concentration of each compound was shown under the columns. To normalize, the relative viability in untreated cells is set as 100%.Abbreviations: GGA, geranylgeranylacetone; IC50, inhibitory concentration at 50% level.

Mentions: We have previously shown that novel synthetic indole compound 1,1,3-tri(3-indolyl)cyclohexane inhibits cancer cell growth in lung cancer cells and xenograft models.36 As an indole compound, indomethacin was reported to induce the expression of HSPs to suppress polyQ aggregation in a cellular model of spinal and bulbar muscular atrophy.37 Indole and synthetic derivative NC001-8 (Figure 1A) were selected to test their potentials to reduce the polyQ aggregation. GGA, a potent HSP inducer,38 was included for comparison. Cell viability assays were performed with human neuroblastoma SH-SY5Y cells after treatment with GGA, indole, or NC001-8 (0.1~100 μM) for 24 hours. The half maximal inhibitory concentrations of the GGA and indoles were calculated using the interpolation method. As shown in Figure 1B, GGA, indole, and NC001-8 had half maximal inhibitory concentrations of 3.02, 0.71, and 0.88 mM, respectively, in SH-SY5Y cells. GGA, indole, and derivative NC001-8 had at least 85% cell viability up to the tested 100 μM, suggesting their low cytotoxicity.


Indole and synthetic derivative activate chaperone expression to reduce polyQ aggregation in SCA17 neuronal cell and slice culture models.

Kung PJ, Tao YC, Hsu HC, Chen WL, Lin TH, Janreddy D, Yao CF, Chang KH, Lin JY, Su MT, Wu CH, Lee-Chen GJ, Hsieh-Li HM - Drug Des Devel Ther (2014)

Indole and derivative NC001-8 and cytotoxicity.Notes: (A) Structure, formula, and molecular weight of indole and synthetic derivative NC001-8. (B) Cytotoxicity of GGA, indole, and NC001-8 against SH-SY5Y cells, using Hoechst-propidium iodide staining. Cells were treated with 100 nM~100 μM tested compounds, and cell proliferation was measured the next day (n=3). The half maximal inhibitory concentration of each compound was shown under the columns. To normalize, the relative viability in untreated cells is set as 100%.Abbreviations: GGA, geranylgeranylacetone; IC50, inhibitory concentration at 50% level.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4206201&req=5

f1-dddt-8-1929: Indole and derivative NC001-8 and cytotoxicity.Notes: (A) Structure, formula, and molecular weight of indole and synthetic derivative NC001-8. (B) Cytotoxicity of GGA, indole, and NC001-8 against SH-SY5Y cells, using Hoechst-propidium iodide staining. Cells were treated with 100 nM~100 μM tested compounds, and cell proliferation was measured the next day (n=3). The half maximal inhibitory concentration of each compound was shown under the columns. To normalize, the relative viability in untreated cells is set as 100%.Abbreviations: GGA, geranylgeranylacetone; IC50, inhibitory concentration at 50% level.
Mentions: We have previously shown that novel synthetic indole compound 1,1,3-tri(3-indolyl)cyclohexane inhibits cancer cell growth in lung cancer cells and xenograft models.36 As an indole compound, indomethacin was reported to induce the expression of HSPs to suppress polyQ aggregation in a cellular model of spinal and bulbar muscular atrophy.37 Indole and synthetic derivative NC001-8 (Figure 1A) were selected to test their potentials to reduce the polyQ aggregation. GGA, a potent HSP inducer,38 was included for comparison. Cell viability assays were performed with human neuroblastoma SH-SY5Y cells after treatment with GGA, indole, or NC001-8 (0.1~100 μM) for 24 hours. The half maximal inhibitory concentrations of the GGA and indoles were calculated using the interpolation method. As shown in Figure 1B, GGA, indole, and NC001-8 had half maximal inhibitory concentrations of 3.02, 0.71, and 0.88 mM, respectively, in SH-SY5Y cells. GGA, indole, and derivative NC001-8 had at least 85% cell viability up to the tested 100 μM, suggesting their low cytotoxicity.

Bottom Line: The molecular chaperones act in preventing protein aggregation to ameliorate downstream harmful events.We found that indole and NC001-8 up-regulated chaperone expression to reduce polyQ aggregation in neuronal differentiated TBP/Q79 cells.Our results demonstrate how indole and derivative NC001-8 reduce polyQ aggregation to support their therapeutic potentials in SCA17 treatment.

View Article: PubMed Central - PubMed

Affiliation: Department of Life Science, National Taiwan Normal University, Taipei, Taiwan.

ABSTRACT
In spinocerebellar ataxia type 17 (SCA17), the expansion of a translated CAG repeat in the TATA box binding protein (TBP) gene results in a long polyglutamine (polyQ) tract in the TBP protein, leading to intracellular accumulation of aggregated TBP and cell death. The molecular chaperones act in preventing protein aggregation to ameliorate downstream harmful events. In this study, we used Tet-On SH-SY5Y cells with inducible SCA17 TBP/Q79-green fluorescent protein (GFP) expression to test indole and synthetic derivative NC001-8 for neuroprotection. We found that indole and NC001-8 up-regulated chaperone expression to reduce polyQ aggregation in neuronal differentiated TBP/Q79 cells. The effects on promoting neurite outgrowth and on reduction of aggregation on Purkinje cells were also confirmed with cerebellar primary and slice cultures of SCA17 transgenic mice. Our results demonstrate how indole and derivative NC001-8 reduce polyQ aggregation to support their therapeutic potentials in SCA17 treatment.

Show MeSH
Related in: MedlinePlus