Targeting Ubiquitin Proteasome Pathway with Traditional Chinese Medicine for Treatment of Spinocerebellar Ataxia Type 3

I. Cheng Chen, Chia Ning Chang, Wan Ling Chen, Te Hsien Lin, Chih Ying Chao, Chih Hsin Lin, Hsuan Yuan Lin, Mei Ling Cheng, Mu Chun Chiang, Jung Yaw Lin, Yih Ru Wu, Guey Jen Lee-Chen, Chiung Mei Chen

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Abstract

Nine autosomal dominant spinocerebellar ataxias (SCAs) are caused by an abnormal expansion of CAG trinucleotide repeats that encodes a polyglutamine (polyQ) tract within different genes. Accumulation of aggregated mutant proteins is a common feature of polyQ diseases, leading to progressive neuronal dysfunction and degeneration. SCA type 3 (SCA3), the most common form of SCA worldwide, is characterized by a CAG triplet expansion in chromosome 14q32.1 ATXN3 gene. As accumulation of the mutated polyQ protein is a possible initial event in the pathogenic cascade, clearance of aggregated protein by ubiquitin proteasome system (UPS) has been proposed to inhibit downstream detrimental events and suppress neuronal cell death. In this study, Chinese herbal medicine (CHM) extracts were studied for their proteasome-activating, polyQ aggregation-inhibitory and neuroprotective effects in GFP u and ATXN3/Q75-GFP 293/SH-SY5Y cells. Among the 14 tested extracts, 8 displayed increased proteasome activity, which was confirmed by 20S proteasome activity assay and analysis of ubiquitinated and fused GFP proteins in GFP u cells. All the eight extracts displayed good aggregation-inhibitory potential when tested in ATXN3/Q75-GFP 293 cells. Among them, neuroprotective effects of five selected extracts were shown by analyses of polyQ aggregation, neurite outgrowth, caspase 3 and proteasome activities, and ATXN3-GFP, ubiquitin, BCL2 and BAX protein levels in neuronal differentiated ATXN3/Q75-GFP SH-SY5Y cells. Finally, enhanced proteasome function, anti-oxidative activity and neuroprotection of catalpol, puerarin and daidzein (active constituents of Rehmannia glutinosa and Pueraria lobata) were demonstrated in GFP u and/or ATXN3/Q75-GFP 293/SH-SY5Y cells. This study may have therapeutic implication in polyQ-mediated disorders.

Original languageEnglish
Pages (from-to)63-95
Number of pages33
JournalAmerican Journal of Chinese Medicine
Volume47
Issue number1
DOIs
Publication statusPublished - 2019 Jan 1

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Keywords

  • Chinese Herbal Medicine
  • Pueraria lobata/Puerarin and Daidzein
  • Rehmannia glutinosa/Catalpol
  • Spinocerebellar Ataxia Type 3
  • Ubiquitin Proteasome System

ASJC Scopus subject areas

  • Complementary and alternative medicine

Cite this

Chen, I. C., Chang, C. N., Chen, W. L., Lin, T. H., Chao, C. Y., Lin, C. H., Lin, H. Y., Cheng, M. L., Chiang, M. C., Lin, J. Y., Wu, Y. R., Lee-Chen, G. J., & Chen, C. M. (2019). Targeting Ubiquitin Proteasome Pathway with Traditional Chinese Medicine for Treatment of Spinocerebellar Ataxia Type 3. American Journal of Chinese Medicine, 47(1), 63-95. https://doi.org/10.1142/S0192415X19500046