The Role And Mechanism Of ATP13A2 On The Process Of Synucleinopathies Related To Dementia With Lewy Bodies

Parkinson’s disease(PD)is a multi-system disorder,which pathological features are the loss of dopaminergic neurons in substantia nigra and the formation of Lewy bodies.Oxidative stress and acumulation of unfolded protein are involed in pathology of PD,but accurate description of dopaminergic neuron degeneration remains vacant.A growing number of genetic and biochemical research findings suggest that autophagy-lysosome pathway(ALP)dysfunction has an important role in the pathogenesis of PD.Most studies have focused on the neurotoxic cause by secondary accumulation of α-synuclein,while the function of lysosomes was also damaged in PD patients with progress of pathology.It means that ALP dysfunction seems to be available through a variety of mechanisms to cause neurotoxicity.ATP13A2 has a higher expression level in the midbrain of mammals.Mutations of ATP13A2 can lead to neurodegenerative disease called Kufor-Rakeb syndrome(KRS).Wild type ATP13A2 protein partly locates in the lysosome membrane,which is currently estimated to be a cation transporter.The mechanisms which homozygous F182L and G877R missense mutations in ATP13A2 affect autophagy and potentially cause parkinsonism are still unkonwn at present.For this purpose we establish the stable ATP13A2 over-expressing cell line in B103 neuroblastoma cells.We observe ATP13A2 cellular distribution and function.Using β-syn stable over-expressing cell lines,we explore the effect of ATP13A2 wild and mutant protein on synucleinopathies.By immunofluorescence stain and western blotting method in B103 ATP13A2 stable cells,we found that wild type protein of ATP13A2 was gathered and primarily located in lysosome merbrane,and the activity of lysosome was slightly decreased.ATP13A2 F182L and G877R diffused more in the cytoplasm and abnormal stored in endocytoplasmic reticulum(ER).On the other hand,the mutant ATP13A2 reduced mitochondrial continuity and increased cytotoxicity.ATP13A2 mutants induced autophagy and were mainly degraded by ALP.In the β-syn stable neuroblastoma cell lines,mutant ATP13A2 promoted synuclein accumulation to form the inclusion bodies,and enhanced the aggreation of β-syn V70M.ATP13A2 plays an important role in maintaining the activity of lysosomes and mutant ATP13A2 causes endoplasmic reticulum stress,reduces mitochondrial continuity and increases the neurotoxicity in over-expressing ATP13A2 cells.On the other hand,ATP13A2 regulates the degredation of synuclein,and the mutation of ATP13A2 accelerates the cytotoxicity of β-syn V70M in synucleinopathies.