Coptis chinensis rhizome extract up-regulates ATP13A2 and lysosomal function to reduce neuronal vulnerability in α-synuclein-expressing BE(2)-M17 cells

Background and aim Chinese herbal medicine (CHM) extracts have potential as treatments for Parkinson’s disease (PD), but their neuroprotective mechanisms remain unclear. ATPase cation transporter type 13A2 (ATP13A2), a regulator of lysosomal function implicated in α-synuclein pathology, may represent a therapeutic target. This study aimed to identify CHM extracts that enhance ATP13A2 expression and evaluate their neuroprotective effects. Experimental procedures A screening of 23 CHM extracts was conducted using human embryonic kidney 293 (HEK-293) cells expressing green fluorescent protein (GFP) under the control of ATP13A2 promoter. The extract of Coptis chinensis ( C. chinensis ) rhizome and its active constituents—berberine, coptisine, and palmatine—were further evaluated in retinoic acid-differentiated BE(2)-M17 neuronal cells expressing A53T α-synuclein mutation. Results and conclusion The C. chinensis rhizome extract and its constituents increased GFP reporter activity by both high-content imaging (129–187%) and flow cytometry (178–261%), as well as lysosomal fluorescence (128–196%) in HEK-293 cells. In A53T α-synuclein-expressing neuronal cells, these treatments reduced LDH release (from 28% to 16–20%), caspase-3 activity (from 117% to 75–93%), and α-synuclein aggregation (from 19.6% to 14.6–16.1%), while promoting neurite outgrowth (from 19.5 μm to 20.6–22.4 μm). Expression of ATP13A2 (from 63% to 113–128%), lysosomal-associated membrane protein 2A (from 77% to 119–124%), and matured cathepsin D (from 70% to 120–130%) also increased. RNAi-mediated ATP13A2 knockdown diminished these neuroprotective benefits. These findings highlight ATP13A2 as a therapeutic target in PD and suggest C. chinensis rhizome extract and its constituents as potential modulators of lysosomal function.