The potential of indole and a synthetic derivative for polyQ aggregation reduction by enhancement of the chaperone and autophagy systems

Chih Hsin Lin, Yih Ru Wu, Pin Jui Kung, Wan Ling Chen, Li Ching Lee, Te Hsien Lin, Chih Ying Chao, Chiung Mei Chen, Kuo Hsuan Chang, Donala Janreddy, Guey Jen Lee-Chen, Ching Fa Yao

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11 Citations (Scopus)

Abstract

In polyglutamine (polyQ)-mediated disorders, the expansion of translated CAG repeats in the disease genes result in long polyQ tracts in their respective proteins, leading to intracellular accumulation of aggregated polyQ proteins, production of reactive oxygen species, and cell death. The molecular chaperones act in preventing protein misfolding and aggregation, thus inhibiting a wide range of harmful downstream events. In the circumstance of accumulation of aggregated polyQ proteins, the autophagic pathway is induced to degrade the misfolded or aggregated proteins. In this study, we used Flp-In 293/SH-SY5Y cells with inducible SCA3 ATXN3/Q75-GFP expression to test the effect of indole and synthetic derivatives for neuroprotection. We found that ATXN3/Q75 aggregation can be significantly prohibited in Flp-In 293 cells by indole and derivative NC001-8. Meanwhile, indole and NC001-8 up-regulated chaperones and autophagy in the same cell models. Both of them further promote neurite outgrowth in neuronal differentiated SH-SY5Y ATXN3/Q75-GFP cells. Our results demonstrate how indole and derivative NC001-8 are likely to work in reduction of polyQ-aggregation and provide insight into the possible effectual mechanism of indole compounds in polyQ spinocerebellar ataxia (SCA) patients. These findings may have therapeutic applications in a broad range of clinical situations. (Chemical Equation Presented).

Original languageEnglish
Pages (from-to)1063-1074
Number of pages12
JournalACS Chemical Neuroscience
Volume5
Issue number10
DOIs
Publication statusPublished - 2014 Oct 15

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Keywords

  • indole and derivative
  • polyQ expansion
  • Spinocerebellar ataxia
  • therapeutics

ASJC Scopus subject areas

  • Biochemistry
  • Physiology
  • Cognitive Neuroscience
  • Cell Biology

Cite this

Lin, C. H., Wu, Y. R., Kung, P. J., Chen, W. L., Lee, L. C., Lin, T. H., Chao, C. Y., Chen, C. M., Chang, K. H., Janreddy, D., Lee-Chen, G. J., & Yao, C. F. (2014). The potential of indole and a synthetic derivative for polyQ aggregation reduction by enhancement of the chaperone and autophagy systems. ACS Chemical Neuroscience, 5(10), 1063-1074. https://doi.org/10.1021/cn500075u