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- Title
Targeting Ubiquitin Proteasome Pathway with Traditional Chinese Medicine for Treatment of Spinocerebellar Ataxia Type 3.
- Authors
Chen, I-Cheng; Chang, Chia-Ning; Chen, Wan-Ling; Lin, Te-Hsien; Chao, Chih-Ying; Lin, Chih-Hsin; Lin, Hsuan-Yuan; Cheng, Mei-Ling; Chiang, Mu-Chun; Lin, Jung-Yaw; Wu, Yih-Ru; Lee-Chen, Guey-Jen; Chen, Chiung-Mei
- 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 GFPu and ATXN3/Q 7 5 -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 GFPu cells. All the eight extracts displayed good aggregation-inhibitory potential when tested in ATXN3/Q 7 5 -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/Q 7 5 -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 GFPu and/or ATXN3/Q 7 5 -GFP 293/SH-SY5Y cells. This study may have therapeutic implication in polyQ-mediated disorders.
- Subjects
REACTIVE oxygen species; ANIMAL experimentation; ANTIOXIDANTS; BIOLOGICAL assay; CATTLE; SPINOCEREBELLAR ataxia; CHINESE medicine; PROTEINS; PROTEOLYTIC enzymes; RESEARCH funding; STATISTICS; WESTERN immunoblotting; PLANT extracts; DATA analysis; NEUROPROTECTIVE agents; DESCRIPTIVE statistics; ONE-way analysis of variance
- Publication
American Journal of Chinese Medicine, 2019, Vol 47, Issue 1, p63
- ISSN
0192-415X
- Publication type
Article
- DOI
10.1142/S0192415X19500046