Thiol peroxidases ameliorate LRRK2 mutant-induced mitochondrial and dopaminergic neuronal degeneration in Drosophila

Angeles, Dario C.; Ho, Patrick; Chua, Ling Ling; Wang, Cheng; Yap, Yan Wann; Ng, Chee-Hoe; Zhou, Zhidong; Lim, Kah‐Leong; Wszołek, Zbigniew K.; Wang, Hong Y; Tan, Eng King

doi:10.1093/hmg/ddu026

Cited by 44 publications

(46 citation statements)

References 41 publications

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“…While LRRK2 mutants are known to alter ETC function, LRRK2 mutants have been found to alter antioxidant capabilities in mitochondria. For example, LRRK2:G2019S was found to phosphorylate and impair PRDX3 in drosophila brains diminishing organelle oxidant handling capacity . Alternatively, patient‐derived fibroblasts and SH‐SY5Y cells expressing LRRK2:G2019 have elevated levels of uncoupling protein expression, namely UCP2 and UCP4, respectively .…”

Section: Parkinson's Disease Relevant Protein Kinasesmentioning

confidence: 99%

Phosphoregulation on mitochondria: Integration of cell and organelle responses

2019

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Mitochondria are highly integrated organelles that are crucial to cell adaptation and mitigating adverse physiology. Recent studies demonstrate that fundamental signal transduction pathways incorporate mitochondrial substrates into their biological programs. Reversible phosphorylation is emerging as a useful mechanism to modulate mitochondrial function in accordance with cellular changes. Critical serine/threonine protein kinases, such as the c‐Jun N‐terminal kinase (JNK), protein kinase A (PKA), PTEN‐induced kinase‐1 (PINK1), and AMP‐dependent protein kinase (AMPK), readily translocate to the outer mitochondrial membrane (OMM), the interface of mitochondria‐cell communication. OMM protein kinases phosphorylate diverse mitochondrial substrates that have discrete effects on organelle dynamics, protein import, respiratory complex activity, antioxidant capacity, and apoptosis. OMM phosphorylation events can be tempered through the actions of local protein phosphatases, such as mitogen‐activated protein kinase phosphatase‐1 (MKP‐1) and protein phosphatase 2A (PP2A), to regulate the extent and duration of signaling. The central mediators of OMM signal transduction are the scaffold proteins because the relative abundance of these accessory proteins determines the magnitude and duration of a signaling event on the mitochondrial surface, which dictates the biological outcome of a local signal transduction pathway. The concentrations of scaffold proteins, such as A‐kinase anchoring proteins (AKAPs) and Sab (or SH3 binding protein 5—SH3BP5), have been shown to influence neuronal survival and vulnerability, respectively, in models of Parkinson's disease (PD), highlighting the importance of OMM signaling to health and disease. Despite recent progress, much remains to be discovered concerning the mechanisms of OMM signaling. Nonetheless, enhancing beneficial OMM signaling events and inhibiting detrimental protein‐protein interactions on the mitochondrial surface may represent highly selective approaches to restore mitochondrial health and homeostasis and mitigate organelle dysfunction in conditions such as PD.

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Section: Parkinson's Disease Relevant Protein Kinasesmentioning

confidence: 99%

Phosphoregulation on mitochondria: Integration of cell and organelle responses

2019

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“…Proper functioning of mitochondria is critical for control of fundamental cellular processes and regulation of pathways that determine cell life or death, while malfunctioning is associated with a number of disorders, such as chronic inflammation and premature senescence (15,16). Normal functioning of mitochondria requires peroxidase activity in the form of peroxiredoxins and/or glutathione peroxidases (17).…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial peroxiredoxins are essential in regulating the relationship between Drosophila immunity and aging

Odnokoz

Nakatsuka

Klichko

et al. 2017

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Previously, we have shown that flies under-expressing the two mitochondrial peroxiredoxins (Prxs), dPrx3 and dPrx5, display increases in tissue-specific apoptosis and dramatically shortened life span, associated with a redox crisis, manifested as changes in GSH:GSSG and accumulation of protein mixed disulfides. To identify specific pathways responsible for the observed biological effects, we performed a transcriptome analysis. Functional clustering revealed a prominent group enriched for immunity-related genes, including a considerable number of NF-kB-dependent antimicrobial peptides (AMP) that are up-regulated in the Prx double mutant. Using qRT-PCR analysis we determined that the age-dependent changes in AMP levels in mutant flies were similar to those observed in controls when scaled to percentage of life span. To further clarify the role of Prx-dependent mitochondrial signaling, we expressed different forms of dPrx5, which unlike the uniquely mitochondrial dPrx3 is found in multiple subcellular compartments, including mitochondrion, nucleus and cytosol. Ectopic expression of dPrx5 in mitochondria but not nucleus or cytosol partially extended longevity under normal or oxidative stress conditions while complete restoration of life span occurred when all three forms of dPrx5 were expressed from the wild type dPrx5 transgene. When dPrx5 was expressed in mitochondria or in all three compartments, it substantially delayed the development of hyperactive immunity while expression of cytosolic or nuclear forms had no effect on the immune phenotype. The data suggest a critical role of mitochondria in development of chronic activation of the immune response triggered by impaired redox control.

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“…Mutations in LRRK2 are shown to cause autosomal dominant PD in humans, and over-expression of mutant LRRK2 results in dysfunction of dopamine signaling or degeneration of dopaminergic neurons in animal models of PD [5, 6, 7, 8, 9]. Mutations in DJ-1 result in autosomal recessive, early onset PD in humans, through destabilization and loss of DJ-1 protein content [10].…”

Section: Introductionmentioning

confidence: 99%

Regulation of DJ-1 by Glutaredoxin 1 in Vivo: Implications for Parkinson’s Disease

et al. 2016

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Parkinson’s disease (PD) is the second most common neurodegenerative disease worldwide, caused by the degeneration of the dopaminergic neurons in the substantia nigra. Mutations in PARK7 (DJ-1) result in early onset autosomal recessive PD, and oxidative modification of DJ-1 has been reported to regulate the protective activity of DJ-1 in vitro. Glutathionylation is a prevalent redox modification of proteins resulting from the disulfide adduction of the glutathione moiety to a reactive cysteine-SH; and glutathionylation of specific proteins has been implicated in regulation of cell viability. Glutaredoxin 1 (Grx1) is the principal deglutathionylating enzyme within cells, and it has been reported to mediate protection of dopaminergic neurons in C. elegans, however many of the functional downstream targets of Grx1 in vivo remain unknown. Previously, DJ-1 protein content was shown to decrease concomitantly with diminution of Grx1 protein content in cell culture of model neurons (SH-SY5Y and Neuro-2A lines). In the current study we aimed to investigate the regulation of DJ-1 by Grx1 in vivo and characterize its glutathionylation in vitro. Here, with Grx−/− mice we provide evidence that Grx1 regulates protein levels of DJ-1 in vivo. Furthermore, with model neuronal cells (SH-SY5Y) we observed decreased DJ-1 protein content in response to treatment with known glutathionylating agents; and with isolated DJ-1 we identified two distinct sites of glutathionylation. Finally, we found that overexpression of DJ-1 in the dopaminergic neurons partly compensates for the loss of the Grx1 homolog in a C. elegans in vivo model of PD. Therefore; our results reveal a novel redox modification of DJ-1 and suggest a novel regulatory mechanism for DJ-1 content in vivo.

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Thiol peroxidases ameliorate LRRK2 mutant-induced mitochondrial and dopaminergic neuronal degeneration in Drosophila

Cited by 44 publications

References 41 publications

Phosphoregulation on mitochondria: Integration of cell and organelle responses

Phosphoregulation on mitochondria: Integration of cell and organelle responses

Mitochondrial peroxiredoxins are essential in regulating the relationship between Drosophila immunity and aging

Regulation of DJ-1 by Glutaredoxin 1 in Vivo: Implications for Parkinson’s Disease

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