Parkinson's disease-associated human ATP13A2 (PARK9) deficiency causes zinc dyshomeostasis and mitochondrial dysfunction

Jin-Sung Park,Carolyn M Sue,David Veivers,Brianada Koentjoro,Alan Mackay-Sim

doi:10.1093/hmg/ddt623

Jin-Sung Park, Carolyn M Sue + Show 3 more

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https://doi.org/10.1093/hmg/ddt623

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Abstract

Human ATP13A2 (PARK9), a lysosomal type 5 P-type ATPase, has been associated with autosomal recessive early-onset Parkinson's disease (PD). ATP13A2 encodes a protein that is highly expressed in neurons and is predicted to function as a cation pump, although the substrate specificity remains unclear. Accumulation of zinc and mitochondrial dysfunction are established aetiological factors that contribute to PD; however, their underlying molecular mechanisms are largely unknown. Using patient-derived human olfactory neurosphere cultures, which harbour loss-of-function mutations in both alleles of ATP13A2, we identified a low intracellular free zinc ion concentration ([Zn2+]i), altered expression of zinc transporters and impaired sequestration of Zn2+ into autophagy-lysosomal pathway-associated vesicles, indicating that zinc dyshomeostasis occurs in the setting of ATP13A2 deficiency. Pharmacological treatments that increased [Zn2+]i also induced the production of reactive oxygen species and aggravation of mitochondrial abnormalities that gave rise to mitochondrial depolarization, fragmentation and cell death due to ATP depletion. The toxic effect of Zn2+ was blocked by ATP13A2 overexpression, Zn2+ chelation, antioxidant treatment and promotion of mitochondrial fusion. Taken together, these results indicate that human ATP13A2 deficiency results in zinc dyshomeostasis and mitochondrial dysfunction. Our data provide insights into the molecular mechanisms of zinc dyshomeostasis in PD and its contribution to mitochondrial dysfunction with ATP13A2 as a molecular link between the two distinctive aetiological factors of PD.

Highlights

Parkinson’s disease (PD) is the most common movement disorder, typically identified with clinical manifestations of tremor, bradykinesia, rigidity and postural instability
These results indicate that human ATP13A2 deficiency results in zinc dyshomeostasis and mitochondrial dysfunction
Pharmacological treatments that elevated the [Zn2+]i were found to exacerbate the loss of mitochondrial function, leading to mitochondrial fragmentation and cell death as a result of ATP depletion. These findings indicate that loss of human ATP13A2 causes zinc dyshomeostasis and abnormal energy metabolism, providing evidence that ATP13A2 is a molecular link between abnormal zinc metabolism and mitochondrial dysfunction in the pathogenesis of PD

Summary

Introduction

Parkinson’s disease (PD) is the most common movement disorder, typically identified with clinical manifestations of tremor, bradykinesia, rigidity and postural instability. 10% of PD patients have identifiable monogenic causes (familial PD). The ATP13A2 gene (PARK9, MIM# 610513) encodes a lysosomal type 5 P-type ATPase. Mutations in ATP13A2 have been associated with an autosomal recessive levodopa-responsive early-onset parkinsonism, known as Kufor – Rakeb syndrome (KRS, MIM# 606693) [2]. KRS patients present with typical PD manifestations alongside other clinical features such as supranuclear gaze palsy, facial-faucial myoclonus and spasticity [3]. Mutations identified in most KRS patients follow an autosomal recessive trait involving two mutant alleles (homozygotes or compound heterozygotes) that cause mRNA degradation, protein misfolding/truncation and degradation [2,3,4,5].

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