Unlocking ATP13A2/PARK9 activity

Martin, Shaun; Holemans, Tine; Vangheluwe, Peter

doi:10.1080/15384101.2015.1093420

Cited by 11 publications

(13 citation statements)

References 7 publications

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“…Here, we tested whether the activation of ATP13A2 during metal toxicity also depends on PA and/or PI(3,5)P2. In the stable SHSY5Y cell lines we observed that similar to rotenone and MPP+ toxicity ATP13A2 overexpression protected against, whereas KD sensitized cells to metal toxicity following exposure to Zn 2+ , Mn 2+ , and Fe 3+ (Figures 4(a) and 4(b) ), in line with previous reports [ 14 , 16 , 17 , 19 , 23 ].…”

Section: Resultssupporting

confidence: 92%

“…The catalytic activity of ATP13A2 provides cellular protection against various PD-related insults like mitochondrial stress [ 14 , 23 ] and metal exposure (Mn 2+ [ 16 , 17 ], Zn 2+ [ 18 ], and Fe 3+ [ 19 ]). Here we established that these various cytoprotective effects depend on the same activation mechanism of ATP13A2 involving an N-terminal lipid switch.…”

Section: Discussionmentioning

confidence: 99%

“…SHSY5Y neuroblastoma cell lines stably expressing firefly luciferase (FLUC, control), WT ATP13A2, mutants of the three putative N-terminal LBS (LBS1: 65 FRWKP→FAWAP; LBS2: 74 RLRLR→ALALA; LBS3: 155 KRVLR→AAVLA; LBS1.2.3: combination of LBS1–3 mutations), or sh-ATP13A2 (KD [ 14 , 23 ]) were generated via lentiviral transduction and maintained as described previously [ 14 ].…”

Section: Methodsmentioning

confidence: 99%

“…Furthermore, knockdown (KD) of ATP13A2 in mouse cortical neurons or human neuroblastoma SHSY5Y cells triggers mitochondrial fragmentation and ROS production [ 22 ], whereas ATP13A2 deficiency in patient-derived olfactory neurosphere cultures results in Zn 2+ dyshomeostasis, which contributes to mitochondrial dysfunction [ 18 ]. Finally, in a cellular PD model in which SHSY5Y cells were exposed to the mitochondrial complex I inhibitor rotenone to induce mitochondrial stress, ATP13A2 activity confers cytoprotection, since overexpression of WT ATP13A2, but not a catalytic dead mutant, protects against, whereas KD of ATP13A2 exacerbates cell toxicity [ 14 , 23 ].…”

Section: Introductionmentioning

confidence: 99%

“…The phosphoinositide PI(3,5)P2 is formed by the PIKfyve lipid kinase and mainly resides in the late endo-/lysosomes where it functions as an organelle tag. Pharmacological inhibition of PLD (to prevent PA production) or PIKfyve (to prevent PI(3,5)P2 generation) counteracts the ATP13A2-mediated protective effect on rotenone-induced mitochondrial toxicity [ 14 , 23 ]. Together, these results indicate that PA and PI(3,5)P2 are required for the activation of ATP13A2 in conditions of mitochondrial stress.…”

Section: Introductionmentioning

confidence: 99%

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Protection against Mitochondrial and Metal Toxicity Depends on Functional Lipid Binding Sites in ATP13A2

Martin

Veen

Holemans

et al. 2016

Parkinson's Disease

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The late endo-/lysosomal P-type ATPase ATP13A2 (PARK9) is implicated in Parkinson's disease (PD) and Kufor-Rakeb syndrome, early-onset atypical Parkinsonism. ATP13A2 interacts at the N-terminus with the signaling lipids phosphatidic acid (PA) and phosphatidylinositol (3,5) bisphosphate (PI(3,5)P2), which modulate ATP13A2 activity under cellular stress conditions. Here, we analyzed stable human SHSY5Y cell lines overexpressing wild-type (WT) or ATP13A2 mutants in which three N-terminal lipid binding sites (LBS1–3) were mutated. We explored the regulatory role of LBS1–3 in the cellular protection by ATP13A2 against mitochondrial stress induced by rotenone and found that the LBS2-3 mutants displayed an abrogated protective effect. Moreover, in contrast to WT, the LBS2 and LBS3 mutants responded poorly to pharmacological inhibition of, respectively, PI(3,5)P2 and PA formation. We further demonstrate that PA and PI(3,5)P2 are also required for the ATP13A2-mediated protection against the toxic metals Mn2+, Zn2+, and Fe3+, suggesting a general lipid-dependent activation mechanism of ATP13A2 in various PD-related stress conditions. Our results indicate that the ATP13A2-mediated protection requires binding of PI(3,5)P2 to LBS2 and PA to LBS3. Thus, targeting the N-terminal lipid binding sites of ATP13A2 might offer a therapeutic approach to reduce cellular toxicity of various PD insults including mitochondrial stress.

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Section: Resultssupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Protection against Mitochondrial and Metal Toxicity Depends on Functional Lipid Binding Sites in ATP13A2

Martin

Veen

Holemans

et al. 2016

Parkinson's Disease

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ATP13A2 is a Prognostic Biomarker and Correlates with Immune Infiltrates in Hepatocellular Carcinoma

Huang

Zhou

et al. 2023

Journal of Gastrointestinal Surgery

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Exacerbation of sensorimotor dysfunction in mice deficient in Atp13a2 and overexpressing human wildtype alpha-synuclein

Dirr

Ekhator

Blackwood

et al. 2018

Behavioural Brain Research

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Loss of function mutations in the gene ATP13A2 are associated with Kufor-Rakeb Syndrome and Neuronal Ceroid Lipofuscinosis, the former designated as an inherited form of Parkinson's disease (PD). The function of ATP13A2 is unclear but in vitro studies indicate it is a lysosomal protein and may interact with the presynaptic protein alpha-synuclein (aSyn) and certain heavy metals. Accumulation of aSyn is a major component of lewy bodies, the pathological hallmark of PD. Atp13a2-deficient (13a2) mice develop age-dependent sensorimotor deficits, and accumulation of insoluble aSyn in the brain. To better understand the interaction between ATP13A2 and aSyn, double mutant mice with loss of Atp13a2 function combined with overexpression of human wildtype aSyn were generated. Female and male wildtype (WT), 13a2, aSyn, and 13a2-aSyn mice were tested on a battery of sensorimotor tests including adhesive removal, challenging beam traversal, spontaneous activity, gait, locomotor activity, and nest-building at 2, 4, and 6 months of age. Double mutant mice showed an earlier onset and accelerated alterations in sensorimotor function that were age, sex and test-dependent. Female 13a2-aSyn mice showed early and progressive dysfunction on the beam and in locomotor activity. In males, 13a2-aSyn mice showed more severe impairments in spontaneous activity and adhesive removal. Sex differences were also observed in aSyn and 13a2-aSyn mice on the beam, cylinder, and adhesive removal tests. In other tasks, double mutant mice displayed deficits similar to aSyn mice. These results indicate loss of Atp13a2 function exacerbates the sensorimotor phenotype in aSyn mice in an age and sex-dependent manner.

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Unlocking ATP13A2/PARK9 activity

Cited by 11 publications

References 7 publications

Protection against Mitochondrial and Metal Toxicity Depends on Functional Lipid Binding Sites in ATP13A2

Protection against Mitochondrial and Metal Toxicity Depends on Functional Lipid Binding Sites in ATP13A2

ATP13A2 is a Prognostic Biomarker and Correlates with Immune Infiltrates in Hepatocellular Carcinoma

Exacerbation of sensorimotor dysfunction in mice deficient in Atp13a2 and overexpressing human wildtype alpha-synuclein

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