Objective: Decipher the role of ATP13A2 in Parkinson’s disease.

Background: ATP13A2 is a lysosomal P-type ATPase with significant implications in Parkinson’s disease (PD). Little is known about the structure and function of ATP13A2, yet it plays important roles in homeostasis, underlying a pro-survival phenotype in both in vitro and in vivo models of PD following heavy metals, mitochondrial targeting compounds as well as alpha-synuclein. ATP13A2 plays a significant role in autophagy, exosome biogenesis and mitochondrial/lysosomal regulation. Like other P-type ATPases, ATP13A2 undergoes auto-phosphorylation, which is stimulated by the stress inducible lipids phosphatidic acid (PA) and phosphatidyl inositol (3,5) bisphosphate (PI(3,5)P2) by interacting with the N-terminus of ATP13A2. Our biochemical data further showed that ATP13A2 resides in an inactive conformation and awaits further activation by PA and PI(3,5)P2, potentiating a pro-survival phenotype against mitochondrial dysfunction.

Methods: Stable human neuroblastoma cell lines of ATP13A2 knockdown or WT/mutant overexpression, patient derived fibroblasts with loss of ATP13A2 activity, and Caenorhabditis elegans knockout strains of the ATP13A2 orthologue were subjected to stress conditions including Zn2+, Mn2+ and Fe3+ or mitochondrial toxins (rotenone, rhodamine 6G).

Results: We show that mutation of the N-terminal lipid binding sites prevents the protective effect of ATP13A2 against mitochondrial stress, mimicking the phenotype observed with pharmacological inhibition of PA and PI(3,5)P2 synthesis. This points to an inhibitory effect of the N-terminus on ATP13A2 function. Secondly, we demonstrate that both metal exposure and mitochondrial toxins trigger mitochondrial ROS production, which is sufficient to activate an ATP13A2 dependent protective response in SHSY5Y cells. In contrast, a reduced ATP13A2 expression in SHSY5Y cells, patient-derived fibroblasts or C. elegans KO strains, or an impaired capacity of ATP13A2 to interact with PA or PI(3,5)P2 increases the sensitivity to mitochondrial ROS. Finally, treatment with mitochondrial specific antioxidants phenocopies the protective ATP13A2 effect.

Conclusions: We conclude that ATP13A2 provides protection to mitochondrial ROS, which depends on the lipids PI(3,5)P2 and PA that bind to the ATP13A2 N-terminus. We highlight that ATP13A2 activating compounds may be considered as a therapeutic strategy for PD.

ZING neurodegeneration meeting, Cancun, 2015.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/protective-effects-of-atp13a2-in-parkinsons-disease-models/