Zn²⁺ dyshomeostasis caused by loss of ATP13A2/PARK9 leads to lysosomal dysfunction and alpha-synuclein accumulation

Mutations in ATP13A2 (PARK9) cause Kufor-Rakeb syndrome(KRS) characterized by juvenile-onset parkinsonism, pyramidal signs anddementia.PARK9belongs to type 5 P-type ATPase with its putative function as a cation transporter. Loss of PARK9 leads to lysosomal dysfunction and subsequent α-synuclein (α-Syn) accumulation. However, the mechanistic link between PARK9and lysosomal dysfunction remains unclear. Here,we found that patient fibroblasts expressing mutant PARK9 or primary neurons with silenced PARK9 exhibited increased sensitivity to extracellular zinc (Zn²⁺). This effect was rescued with the Zn²⁺ chelators clioquinol or TPEN. PARK9-deficient cells showed decreased lysosomal sequestration of Zn²⁺ and increased expression of zinc transporters. Importantly, increased concentrations of Zn²⁺ (Zn²⁺ stress) resulted in lysosomal dysfunction that was partially restored by expression of wild-type PARK9. Zn²⁺ stress also caused increased expression of α-Syn and consequently decreased activity of the lysosomal enzyme glucocerebrosidase. Together, these data suggest that PARK9 loss of function leads to dyshomeostasis of intracellular Zn²⁺ that in turn contributes to lysosomal dysfunction and accumulation of α-Syn. It will be of interest to examine whether therapeutic lowering of zinc may prove beneficial for patients with KRS.