1. Indole and synthetic derivative activate chaperone expression to reduce polyQ aggregation in SCA17 neuronal cell and slice culture models.
- Author
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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, and Hsieh-Li HM
- Subjects
- Animals, Antineoplastic Agents chemical synthesis, Antineoplastic Agents chemistry, Cell Proliferation drug effects, Dose-Response Relationship, Drug, Drug Screening Assays, Antitumor, Humans, In Vitro Techniques, Indoles chemical synthesis, Indoles chemistry, Mice, Molecular Chaperones biosynthesis, Neurons cytology, Neurons metabolism, Neurons pathology, Neuroprotective Agents chemical synthesis, Neuroprotective Agents chemistry, Organ Culture Techniques, Peptides chemistry, Protein Aggregation, Pathological pathology, Protein Aggregation, Pathological prevention & control, Protein Binding drug effects, Structure-Activity Relationship, Tumor Cells, Cultured, Antineoplastic Agents pharmacology, Indoles pharmacology, Molecular Chaperones metabolism, Neurons drug effects, Neuroprotective Agents pharmacology, Peptides metabolism, Protein Aggregation, Pathological drug therapy
- 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.
- Published
- 2014
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