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Indole and synthetic derivative activate chaperone expression to reduce polyQ aggregation in SCA17 neuronal cell and slice culture models.
- Source :
-
Drug design, development and therapy [Drug Des Devel Ther] 2014 Oct 16; Vol. 8, pp. 1929-39. Date of Electronic Publication: 2014 Oct 16 (Print Publication: 2014). - Publication Year :
- 2014
-
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.
- 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
Subjects
Details
- Language :
- English
- ISSN :
- 1177-8881
- Volume :
- 8
- Database :
- MEDLINE
- Journal :
- Drug design, development and therapy
- Publication Type :
- Academic Journal
- Accession number :
- 25342886
- Full Text :
- https://doi.org/10.2147/DDDT.S67376