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

Taiji Tsunemi, Dimitri Krainc*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

101 Scopus citations

Abstract

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.

Original languageEnglish
Article numberddt572
Pages (from-to)2791-2801
Number of pages11
JournalHuman Molecular Genetics
Volume23
Issue number11
DOIs
StatePublished - 2014

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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