ATP13A2 Declines Zinc-Induced Accumulation of α-Synuclein in a Parkinson's Disease Model

Parkinson's disease (PD) is characterized by the presence of Lewy bodies caused by alpha-synuclein. The imbalance of zinc homeostasis is a major cause of PD, promoting alpha-synuclein accumulation. ATP13A2, a transporter found in acidic vesicles, plays an important role in Zn2+ homeostasis and is highly expressed in Lewy bodies in PD-surviving neurons. ATP13A2 is involved in the transport of zinc ions in lysosomes and exosomes and inhibits the aggregation of alpha-synuclein. However, the potential mechanism underlying the regulation of zinc homeostasis and alpha-synuclein accumulation by ATP13A2 remains unexplored. We used alpha-synuclein-GFP transgenic mice and HEK293 alpha-synuclein-DsRed cell line as models. The spatial exploration behavior of mice was significantly reduced, and phosphorylation levels of alpha-synuclein increased upon high Zn2+ treatment. High Zn2+ also inhibited the autophagy pathway by reducing LAMP2a levels and changing the expression of LC3 and P62, by reducing mitochondrial membrane potential and increasing the expression of cytochrom C, and by activating the ERK/P38 apoptosis signaling pathway, ultimately leading to increased caspase 3 levels. These protein changes were reversed after ATP13A2 overexpression, whereas ATP13A2 knockout exacerbated alpha-synuclein phosphorylation levels. These results suggest that ATP13A2 may have a protective effect on Zn2+-induced abnormal aggregation of alpha-synuclein, lysosomal dysfunction, and apoptosis.