Abstract

Mutations in ATP13A2 cause Kufor-Rakeb syndrome (KRS), a juvenile form of Parkinson’s disease (PD) with dementia. However, the mechanisms by which mutations in ATP13A2 cause KRS is not understood. The mutations lead to misfolding of the translated Atp13a2 protein and its premature degradation in the endoplasmic reticulum, never reaching the lysosome where the protein is thought to function. Atp13a2 is a P-type ATPase, a class of proteins that function in ion transport. Indeed, studies of human, mouse, and yeast Atp13a2 proteins suggest a possible involvement in regulation of heavy metal toxicity. Here we report on the cytoprotective function of Atp13a2 on HeLa cells and dopamine neurons of Caenorhabditis elegans (C. elegans). HeLa cells stably overexpressing V5- tagged Atp13a2Isoform-1 protein were more resistant to elevated manganese exposure and to starvation-induced cell death compared to cells not overexpressing the protein. Because PD is characterized by loss of dopamine neurons, we generated transgenic C. elegans expressing GFP-tagged human Atp13a2 protein in dopamine neurons. The transgenic animals exhibited higher resistance to dopamine neuron degeneration after acute exposure to manganese compared to nematodes that expressed GFP alone. The results suggest Atp13a2 Isoform-1 protein confers cytoprotection against toxic insults, including those that cause PD syndromes.

Highlights

  • Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by bradykinesia and tremor at rest [1]

  • Because lysosomes play a fundamental role in the survival of cells during nutrient deprivation, we examined whether the increased expression of Atp13a2 protein in lysosomes would protect HeLa cells from starvation-induced cell death

  • We report on the cytoprotective properties conferred by the human Atp13a2Isoform-1 protein in HeLa cells and dopamine neurons of C. elegans

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Summary

Introduction

Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by bradykinesia and tremor at rest [1]. The disease is associated with loss of dopamine neurons in the substantia nigra pars compacta. Besides age, which is a major risk factor for PD, mutations in several genes are linked to the cause of the disease [2, 3]. A small number of cases have been linked to exposure to certain environmental toxins like pesticides and heavy metals. ATP13a2 protection against manganese toxicity [4, 5]. A interesting connection linking genetic and environmental etiology of PD was the discovery that mutations in ATP13A2 cause early-onset PD [6]

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