Protective Effects of Coptis chinensis Rhizome Extract and Its Constituents (Berberine, Coptisine, and Palmatine) against -Synuclein Neurotoxicity in Dopaminergic SH-SY5Y Cells

Parkinson's disease (PD) is a common neurodegenerative disease with progressive loss of dopaminergic neurons in substantia nigra and the presence of alpha-synuclein-immunoreactive inclusions. Gaucher's disease is caused by homozygous mutations in beta-glucocerebrosidase gene (GBA). GBA mutation carriers have an increased risk of PD. Coptis chinensis (C. chinensis) rhizome extract is a major herb widely used to treat human diseases. This study examined the association of GBA L444P mutation with Taiwanese PD in 1016 cases and 539 controls. In addition, the protective effects of C. chinensis rhizome extract and its active constituents (berberine, coptisine, and palmatine) against PD were assayed using GBA reporter cells, LC3 reporter cells, and cells expressing mutated (A53T) alpha-synuclein. Case-control study revealed that GBA L444P carriers had a 3.93-fold increased risk of PD (95% confidence interval (CI): 1.37-11.24, p = 0.006) compared to normal controls. Both C. chinensis rhizome extract and its constituents exhibited chemical chaperone activity to reduce alpha-synuclein aggregation. Promoter reporter and endogenous GBA protein analyses revealed that C. chinensis rhizome extract and its constituents upregulated GBA expression in 293 cells. In addition, C. chinensis rhizome extract and its constituents induced autophagy in DsRed-LC3-expressing 293 cells. In SH-SY5Y cells expressing A53T alpha-synuclein, C. chinensis rhizome extract and its constituents reduced alpha-synuclein aggregation and associated neurotoxicity by upregulating GBA expression and activating autophagy. The results of reducing alpha-synuclein aggregation, enhancing GBA expression and autophagy, and protecting against alpha-synuclein neurotoxicity open up the therapeutic potentials of C. chinensis rhizome extract and constituents for PD.