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

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 75 -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 75 -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 75 -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 75 -GFP 293/SH-SY5Y cells. This study may have therapeutic implication in polyQ-mediated disorders.

• Authors: 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
• Journal: The American journal of Chinese medicine (Am J Chin Med) Vol. 47 Issue 1 Pg. 63-95 ( 2019) ISSN: 1793-6853 [Electronic] Singapore
• PMID: 30612452 (Publication Type: Journal Article)

Chemical References

• Antioxidants
• Drugs, Chinese Herbal
• Iridoid Glucosides
• Isoflavones
• Neuroprotective Agents
• Peptides
• Ubiquitin
• catalpol
• polyglutamine
• daidzein
• Proteasome Endopeptidase Complex
• puerarin

Topics

• Antioxidants
• Cells, Cultured
• Drugs, Chinese Herbal (pharmacology, therapeutic use)
• HEK293 Cells
• Humans
• Iridoid Glucosides (pharmacology, therapeutic use)
• Isoflavones (pharmacology, therapeutic use)
• Machado-Joseph Disease (drug therapy, genetics)
• Molecular Targeted Therapy
• Mutation
• Neuroprotective Agents
• Peptides (genetics, metabolism)
• Phytotherapy
• Proteasome Endopeptidase Complex (metabolism)
• Protein Aggregation, Pathological (metabolism, prevention & control)
• Pueraria (chemistry)
• Rehmannia (chemistry)
• Trinucleotide Repeat Expansion (genetics)
• Ubiquitin (metabolism)