The indole compound NC009-1 inhibits aggregation and promotes neurite outgrowth through enhancement of HSPB1 in SCA17 cells and ameliorates the behavioral deficits in SCA17 mice

Chiung Mei Chen, Wan Ling Chen, Chen Ting Hung, Te Hsien Lin, Chih Ying Chao, Chih Hsin Lin, Yih Ru Wu, Kuo Hsuan Chang, Ching Fa Yao, Guey Jen Lee-Chen, Ming Tsan Su, Hsiu Mei Hsieh-Li

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

Spinocerebellar ataxia type 17 (SCA17) is caused by the expansion of translated CAG repeat in the TATA box binding protein (TBP) gene encoding a long polyglutamine (polyQ) tract in the TBP protein, which leads 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 cells with inducible SCA17 TBP/Q79-GFP expression to test five in-house NC009 indole compounds for neuroprotection. We found that both aggregation and polyQ-induced reactive oxygen species can be significantly prohibited by the tested NC009 compounds in Tet-On TBP/Q79 293 cells. Among the five indole compounds, NC009-1 up-regulated expression of heat shock protein family B (small) member 1 (HSPB1) chaperone to reduce polyQ aggregation and promote neurite outgrowth in neuronal differentiated TBP/Q79 SH-SY5Y cells. The increased HSPB1 thus ameliorated the increased BH3 interacting domain death agonist (BID), cytochrome c (CYCS) release, and caspase 3 (CASP3) activation which result in apoptosis. Knock down of HSPB1 attenuated the effects of NC009-1 on TBP/Q79 SH-SY5Y cells, suggesting that HSPB1 might be one of the major pathways involved for NC009-1 effects. NC009-1 further reduced polyQ aggregation in Purkinje cells and ameliorated behavioral deficits in SCA17 TBP/Q109 transgenic mice. Our results suggest that NC009-1 has a neuroprotective effect on SCA17 cell and mouse models to support its therapeutic potential in SCA17 treatment.

Original languageEnglish
Pages (from-to)259-269
Number of pages11
JournalNeuroToxicology
Volume67
DOIs
Publication statusPublished - 2018 Jul 1

Fingerprint

TATA-Box Binding Protein
Agglomeration
Molecular Chaperones
Gene encoding
indole
Spinocerebellar Ataxia 17
Neuronal Outgrowth
Purkinje Cells
Neuroprotective Agents
Cell death
Heat-Shock Proteins
Cytochromes c
Caspase 3
Transgenic Mice
Reactive Oxygen Species
Proteins
Cell Death
Chemical activation
polyglutamine
Apoptosis

Keywords

  • HSPB1
  • Indole compound
  • PolyQ aggregation
  • Spinocerebellar ataxia type 17
  • TATA box binding protein
  • Therapeutics

ASJC Scopus subject areas

  • Neuroscience(all)
  • Toxicology

Cite this

The indole compound NC009-1 inhibits aggregation and promotes neurite outgrowth through enhancement of HSPB1 in SCA17 cells and ameliorates the behavioral deficits in SCA17 mice. / Chen, Chiung Mei; Chen, Wan Ling; Hung, Chen Ting; Lin, Te Hsien; Chao, Chih Ying; Lin, Chih Hsin; Wu, Yih Ru; Chang, Kuo Hsuan; Yao, Ching Fa; Lee-Chen, Guey Jen; Su, Ming Tsan; Hsieh-Li, Hsiu Mei.

In: NeuroToxicology, Vol. 67, 01.07.2018, p. 259-269.

Research output: Contribution to journalArticle

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abstract = "Spinocerebellar ataxia type 17 (SCA17) is caused by the expansion of translated CAG repeat in the TATA box binding protein (TBP) gene encoding a long polyglutamine (polyQ) tract in the TBP protein, which leads 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 cells with inducible SCA17 TBP/Q79-GFP expression to test five in-house NC009 indole compounds for neuroprotection. We found that both aggregation and polyQ-induced reactive oxygen species can be significantly prohibited by the tested NC009 compounds in Tet-On TBP/Q79 293 cells. Among the five indole compounds, NC009-1 up-regulated expression of heat shock protein family B (small) member 1 (HSPB1) chaperone to reduce polyQ aggregation and promote neurite outgrowth in neuronal differentiated TBP/Q79 SH-SY5Y cells. The increased HSPB1 thus ameliorated the increased BH3 interacting domain death agonist (BID), cytochrome c (CYCS) release, and caspase 3 (CASP3) activation which result in apoptosis. Knock down of HSPB1 attenuated the effects of NC009-1 on TBP/Q79 SH-SY5Y cells, suggesting that HSPB1 might be one of the major pathways involved for NC009-1 effects. NC009-1 further reduced polyQ aggregation in Purkinje cells and ameliorated behavioral deficits in SCA17 TBP/Q109 transgenic mice. Our results suggest that NC009-1 has a neuroprotective effect on SCA17 cell and mouse models to support its therapeutic potential in SCA17 treatment.",
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AU - Lin, Chih Hsin

AU - Wu, Yih Ru

AU - Chang, Kuo Hsuan

AU - Yao, Ching Fa

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AU - Su, Ming Tsan

AU - Hsieh-Li, Hsiu Mei

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