Single heterozygous mutations in atp13a2 cause mitochondrial dysfunction

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Bi-allelic mutations in ATP13A2 have been associated with Kufor-Rakeb syndrome, an autosomal recessive juvenile-onset Parkinson’s disease (PD). Interestingly, several studies have reported the development of PD in single heterozygous ATP13A2 mutation (sHTZ-PK9) carriers, suggesting their role as a risk factor for PD. However, the pathogenicity of these mutations remained unexplored. To understand the role of these mutations in PD, therefore, we tested whether sHTZ-PK9 impairs cellular function associated with PD.


We determined the extent of mitochondrial dysfunction in skin fibroblast lines derived from three single heterozygous ATP13A2 mutation sHTZ-PK9 carriers (one carrier harbouring c.3176T>G and two carriers with c.3057delC) and healthy controls (n=3). In addition, we also assessed possible alterations in Zn2+ metabolism.


The level of total ATP13A2 transcripts was lower in cells carrying the c.3057delC mutation in ATP13A2 compared with controls, while it was higher in cells carrying the c.3176T>G mutation with both wild-type and mutant transcripts elevated to a similar level. When mitochondrial oxygen consumption rate (OCR) was measured, sHTZ-PK9 cells showed a significant decrease in the maximal OCR. Furthermore, ATP production rate and mitochondrial membrane potential, as well as mitochondrial network interconnectivity, were also reduced in the sHTZ-PK9 cells, indicating mitochondrial dysfunction. However, the level of reactive oxygen species remained unchanged. In addition, sHTZ-PK9 cells showed decreased transcripts of zinc transporters and increased cytotoxicity to ZnCl2 treatment, suggesting Zn2+ dyshomeostasis, while the intracellular free Zn2+ levels were normal in sHTZ-PK9 cells.


Our results indicate mitochondrial dysfunction in skin fibroblasts carrying single heterozygous ATP13A2 mutations despite a differential effect of the mutations on ATP13A2 expression. Given that impaired Zn2+ homeostasis is detected in sHTZ-PK9 cells, it is possible that altered Zn2+ metabolism underlies mitochondrial dysfunction. Collectively, these findings support that single heterozygous ATP13A2 mutations function as a risk factor for PD.

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