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

Human Molecular Genetics
Taiji Tsunemi, Dimitri Krainc

Abstract

Mutations in ATP13A2 (PARK9) cause Kufor-Rakeb syndrome (KRS) characterized by juvenile-onset parkinsonism, pyramidal signs and dementia. PARK9 belongs 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 PARK9 and 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 (Zn(2+)). This effect was rescued with the Zn(2+) chelators clioquinol or TPEN. PARK9-deficient cells showed decreased lysosomal sequestration of Zn(2+) and increased expression of zinc transporters. Importantly, increased concentrations of Zn(2+) (Zn(2+) stress) resulted in lysosomal dysfunction that was partially restored by expression of wild-type PARK9. Zn(2+) 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 Zn(2+) that in turn contributes to lysosomal dysfunction and accumulation of α-Syn. It ...Continue Reading

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