Caffeic acid reduces A53T α-synuclein by activating JNK/Bcl-2-mediated autophagy in vitro and improves behaviour and protects dopaminergic neurons in a mouse model of Parkinson's disease

The human A53T mutant of alpha-synuclein tends to aggregate and leads to neurotoxicity in familial Parkinson's disease (PD). The aggregation of alpha-synuclein is also found in sporadic PD. Thus, targeting alpha-synuclein clearance could be used as a drug-discovery strategy for PD treatment. Caffeic acid (CA) has shown neuroprotection in Alzheimer's disease or cerebral ischaemia; however, it is unclear whether CA confers neuroprotection in alpha-synuclein-induced PD models. Here we focus on whether and how A53T alpha-synuclein is affected by CA. We assessed the effect of CA on cell viability in SH-SY5Y cells overexpressing A53T alpha-synuclein. Pathway-related inhibitors were used to identify the autophagy mechanisms. Seven-month-old A53T alpha-synuclein transgenic mice (A53T Tg mice) received CA daily for eight consecutive weeks. Behaviour tests including the buried food pellet test, the pole test, the Rotarod test, open field analysis, and gait analysis were used to evaluate the neuroprotective effect of CA. Tyrosine hydroxylase and alpha-synuclein were assessed by immunohistochemistry or western blot in the substantia nigra (SN). We found that CA alleviated the cell damage induced by overexpressing A53T alpha-synuclein and that CA reduced A53T alpha-synuclein by activating the JNK/Bcl-2-mediated autophagy pathway. The efficacy of CA on A53T alpha-synuclein degradation was reversed by the autophagy inhibitor bafilomycin Al and the JNK inhibitor SP600125. In A53T Tg mice, CA improved behavioural impairments, attenuated loss of dopaminergic neurons, enhanced autophagy and reduced alpha-synuclein in the SN. Thus, the results provide scientific evidence for the neuroprotective effect of CA in PD. Our work lays the foundation for CA clinical trials to treat PD in the future.