ATP13A2-mediated endo-lysosomal polyamine export counters mitochondrial oxidative stress

Vrijsen, Stephanie; Besora-Casals, Laura; Veen, Sarah van; Zielich, Jeffrey; Haute, Chris Van den; Hamouda, Norin Nabil; Fischer, Christian; Ghesquière, Bart; Tournev, Ivailo; Agostinis, Patrizia; Baekelandt, Veerle; Eggermont, Jan; Lambie, Eric J.; Martin, Shaun; Vangheluwe, Peter

doi:10.1073/pnas.1922342117

Cited by 71 publications

(55 citation statements)

References 77 publications

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“…ATP13A2 knockdown induces a stress response after exposure to rotenone. Studies in C. elegans identified a conserved cell-protective pathway that alleviates mitochondrial oxidative stress via ATP13A2-mediated lysosomal spermine export [ 38 ].…”

Section: Studies With Nematode C Elegans Brougmentioning

confidence: 99%

Invertebrate Models Untangle the Mechanism of Neurodegeneration in Parkinson’s Disease

Surguchov

2021

Cells

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Parkinson’s disease (PD) is the second most common neurodegenerative disease, afflicting ~10 million people worldwide. Although several genes linked to PD are currently identified, PD remains primarily an idiopathic disorder. Neuronal protein α-synuclein is a major player in disease progression of both genetic and idiopathic forms of PD. However, it cannot alone explain underlying pathological processes. Recent studies demonstrate that many other risk factors can accelerate or further worsen brain dysfunction in PD patients. Several PD models, including non-mammalian eukaryotic organisms, have been developed to identify and characterize these factors. This review discusses recent findings in three PD model organisms, i.e., yeast, Drosophila, and Caenorhabditis elegans, that opened new mechanisms and identified novel contributors to this disorder. These non-mammalian models share many conserved molecular pathways and cellular processes with humans. New players affecting PD pathogenesis include previously unknown genes/proteins, novel signaling pathways, and low molecular weight substances. These findings might respond to the urgent need to discover novel drug targets for PD treatment and new biomarkers for early diagnostics of this disease. Since the study of neurodegeneration using simple eukaryotic organisms brought a huge amount of information, we include only the most recent or the most important relevant data.

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Section: Studies With Nematode C Elegans Brougmentioning

confidence: 99%

Invertebrate Models Untangle the Mechanism of Neurodegeneration in Parkinson’s Disease

Surguchov

2021

Cells

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“…ATP13A2 has also been suggested to regulate multiple cellular functions related to lysosomes, including heavy metal homeostasis and mitochondrial homeostasis ( 15 , 122 ). For example, a recent study using SH-SY5Y cells, patient-derived fibroblasts and the nematode C. elegans has identified a conserved cell protective pathway that counters mitochondrial oxidative stress via ATP13A2-mediated lysosomal spermine export ( 123 ).…”

Section: Atp13a2: a Unique Cation Transporter On Lysosomesmentioning

confidence: 99%

Targeting of Lysosomal Pathway Genes for Parkinson's Disease Modification: Insights From Cellular and Animal Models

Abe

Kuwahara

2021

Front. Neurol.

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Previous genetic studies on hereditary Parkinson's disease (PD) have identified a set of pathogenic gene mutations that have strong impacts on the pathogenicity of PD. In addition, genome-wide association studies (GWAS) targeted to sporadic PD have nominated an increasing number of genetic variants that influence PD susceptibility. Although the clinical and pathological characteristics in hereditary PD are not identical to those in sporadic PD, α-synuclein, and LRRK2 are definitely associated with both types of PD, with LRRK2 mutations being the most frequent cause of autosomal-dominant PD. On the other hand, a significant portion of risk genes identified from GWAS have been associated with lysosomal functions, pointing to a critical role of lysosomes in PD pathogenesis. Experimental studies have suggested that the maintenance or upregulation of lysosomal activity may protect against neuronal dysfunction or degeneration. Here we focus on the roles of representative PD gene products that are implicated in lysosomal pathway, namely LRRK2, VPS35, ATP13A2, and glucocerebrosidase, and provide an overview of their disease-associated functions as well as their cooperative actions in the pathogenesis of PD, based on the evidence from cellular and animal models. We also discuss future perspectives of targeting lysosomal activation as a possible strategy to treat neurodegeneration.

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“…Polyamines (putrescine, spermidine, and SPM) are involved in many cellular processes, including cell proliferation and differentiation, modulation of ion channels and receptors, and regulation of gene transcription and translation [ 33 ]. SPM is an antioxidant under physiological conditions [ 34 ], and we recently showed that ATP13A2-mediated SPM transport counteracts mitochondrial oxidative stress [ 35 ]. However, at high concentration, SPM exerts toxic effects, possibly due to lysosomal accumulation and lysosomal-dependent cell death [ 32 ].…”

Section: Introductionmentioning

confidence: 99%

ATP13A2 Regulates Cellular α-Synuclein Multimerization, Membrane Association, and Externalization

Haute

Lobbestael

et al. 2021

IJMS

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ATP13A2, a late endo-/lysosomal polyamine transporter, is implicated in a variety of neurodegenerative diseases, including Parkinson’s disease and Kufor–Rakeb syndrome, an early-onset atypical form of parkinsonism. Loss-of-function mutations in ATP13A2 result in lysosomal deficiency as a consequence of impaired lysosomal export of the polyamines spermine/spermidine. Furthermore, accumulating evidence suggests the involvement of ATP13A2 in regulating the fate of α-synuclein, such as cytoplasmic accumulation and external release. However, no consensus has yet been reached on the mechanisms underlying these effects. Here, we aimed to gain more insight into how ATP13A2 is linked to α-synuclein biology in cell models with modified ATP13A2 activity. We found that loss of ATP13A2 impairs lysosomal membrane integrity and induces α-synuclein multimerization at the membrane, which is enhanced in conditions of oxidative stress or exposure to spermine. In contrast, overexpression of ATP13A2 wildtype (WT) had a protective effect on α-synuclein multimerization, which corresponded with reduced αsyn membrane association and stimulation of the ubiquitin-proteasome system. We also found that ATP13A2 promoted the secretion of α-synuclein through nanovesicles. Interestingly, the catalytically inactive ATP13A2 D508N mutant also affected polyubiquitination and externalization of α-synuclein multimers, suggesting a regulatory function independent of the ATPase and transport activity. In conclusion, our study demonstrates the impact of ATP13A2 on α-synuclein multimerization via polyamine transport dependent and independent functions.

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ATP13A2-mediated endo-lysosomal polyamine export counters mitochondrial oxidative stress

Cited by 71 publications

References 77 publications

Invertebrate Models Untangle the Mechanism of Neurodegeneration in Parkinson’s Disease

Invertebrate Models Untangle the Mechanism of Neurodegeneration in Parkinson’s Disease

Targeting of Lysosomal Pathway Genes for Parkinson's Disease Modification: Insights From Cellular and Animal Models

ATP13A2 Regulates Cellular α-Synuclein Multimerization, Membrane Association, and Externalization

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