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https://www.readbyqxmd.com/read/29234155/analysis-of-neuronal-phosphoproteome-reveals-pink1-regulation-of-bad-function-and-cell-death
#1
Huida Wan, Bin Tang, Xun Liao, Qiufang Zeng, Zhuohua Zhang, Lujian Liao
PINK1 mutations that disrupt its kinase activity cause autosomal recessive early onset Parkinson's disease (PD). Although research in recent years has elucidated a PINK1-Parkin pathway of mitophagy activation that requires PINK1 kinase activity, mitophagy-independent functions of PINK1 and their possible roles in PD pathogenesis have been proposed. Using an unbiased quantitative mass spectrometry approach to analyze the phosphoproteome in primary neurons from wild type and Pink1 knockout mice after mitochondrial depolarization, we uncovered PINK1-regulated phosphorylation sites, which involve coordinated activation of multiple signaling pathways that control cellular response to stress...
December 12, 2017: Cell Death and Differentiation
https://www.readbyqxmd.com/read/29229974/ensemble-modeling-approach-targeting-heterogeneous-rna-seq-data-application-to-melanoma-pseudogenes
#2
Enrico Capobianco, Camilo Valdes, Samanta Sarti, Zhijie Jiang, Laura Poliseno, Nicolas F Tsinoremas
We studied the transcriptome landscape of skin cutaneous melanoma (SKCM) using 103 primary tumor samples from TCGA, and measured the expression levels of both protein coding genes and non-coding RNAs (ncRNAs). In particular, we emphasized pseudogenes potentially relevant to this cancer. While cataloguing the profiles based on the known biotypes, all the employed RNA-Seq methods generated just a small consensus of significant biotypes. We thus designed an approach to reconcile the profiles from all methods following a simple strategy: we selected genes that were confirmed as differentially expressed by the ensemble predictions obtained in a regression model...
December 11, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29229503/characterization-of-early-onset-motor-deficits-in-the-pink1-mouse-model-of-parkinson-disease
#3
Cynthia A Kelm-Nelson, Alexander F L Brauer, Kelsey J Barth, Jacob M Lake, Mackenzie L K Sinnen, Forrest J Stehula, Cagla Muslu, Roberta Marongiu, Michael G Kaplitt, Michelle R Ciucci
In Parkinson disease (PD), a complex neurodegenerative disorder that affects nearly 10 million people worldwide, motor skills are significantly impaired. However, onset and progression of motor deficits and the neural correlates of these deficits are poorly understood. We used a genetic mouse model of PD (Pink1 -/-), with phenotypic similarities to human PD, to investigate the manifestation of early-onset sensorimotor deficits. We hypothesized this mouse model would show early vocalization and gross motor dysfunction that would be progressive in nature...
December 8, 2017: Brain Research
https://www.readbyqxmd.com/read/29226533/the-anthelmintic-drug-niclosamide-and-its-analogues-activate-the-parkinson-s-disease-associated-protein-kinase-pink1
#4
Erica Barini, Ageo Miccoli, Federico Tinarelli, Katie Mulholand, Hachemi Kadri, Farhat Khanim, Laste Stojanovski, Kevin D Read, Kerry Burness, Julian J Blow, Youcef Mehellou, Miratul Muqit
Mutations in PINK1, which impair its catalytic kinase activity, are causal for autosomal recessive early onset Parkinson's disease (PD). Various studies have indicated that the activation of PINK1 could be a useful strategy in treating neurodegenerative diseases such as PD. Herein, we show that the anthelmintic drug niclosamide and its analogues are capable of activating PINK1 in cells via reversible impairment of the mitochondrial membrane potential. Using these compounds, we demonstrate for the first time that the PINK1 pathway is active and detectable in primary neurons...
December 10, 2017: Chembiochem: a European Journal of Chemical Biology
https://www.readbyqxmd.com/read/29219973/vivid-views-of-the-pink1-protein
#5
Salima Daou, Frank Sicheri
No abstract text is available yet for this article.
December 7, 2017: Nature
https://www.readbyqxmd.com/read/29216769/zinc-prevents-mitochondrial-superoxide-generation-by-inducing-mitophagy-in-the-setting-of-hypoxia-reoxygenation-in-cardiac-cells
#6
Xiyun Bian, Tianming Teng, Huanhuan Zhao, Jiangyu Qin, Zhen Qiao, Yuemin Sun, Zhiqiang Liun, Zhelong Xu
Zinc plays a role in autophagy and protects cardiac cells from ischemia/reperfusion injury. This study aimed to test if zinc can induce mitophagy leading to attenuation of mitochondrial superoxide generation in the setting of hypoxia/reoxygenation (H/R) in cardiac cells. H9c2 cells were subjected to 4 h hypoxia followed by 2 h reoxygenation. Under normoxic conditions, treatments of cells with ZnCl2 increased both the LC3-II/LC3-I ratio and GFP-LC3 puncta, implying that zinc induces autophagy. Further experiments showed that endogenous zinc is required for the autophagy induced by starvation and rapamycin...
December 7, 2017: Free Radical Research
https://www.readbyqxmd.com/read/29212708/the-crystal-structure-of-pseudokinase-peak1-sugen-kinase-269-reveals-an-unusual-catalytic-cleft-and-a-novel-mode-of-kinase-fold-dimerization
#7
Byung Hak Ha, Titus J Boggon
The pseudokinase group encompasses some 10% of protein kinases, but pseudokinases diverge from canonical kinases in key motifs. The two members of the small new kinase family 3 (NKF3) group are considered pseudokinases. These proteins, pseudopodium-enriched atypical kinase 1 (PEAK1, Sugen Kinase 269, or SgK269) and pragmin (Sugen Kinase 223 or SgK223) act as scaffolds in growth factor signaling pathways, and both contain a kinase fold with degraded kinase motifs at their C termini. These kinases may harbor regions that mediate oligomerization or control other aspects of signal transduction, but a lack of structural information has precluded detailed investigations into their functional roles...
December 6, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29201272/resveratrol-ameliorates-mitochondrial-elongation-via-drp1-parkin-pink1-signaling-in-senescent-like-cardiomyocytes
#8
Xuecong Ren, Li Chen, Jing Xie, Zhifeng Zhang, Gengting Dong, Jie Liang, Liang Liu, Hua Zhou, Pei Luo
Resveratrol is widely known for its antiaging properties and exerts cardiovascular protective effects in different experimental models. The role of resveratrol in regulating mitochondrial functions and dynamics during the cardiac aging process remains poorly understood. In this study, the effects of resveratrol on mitochondrial morphology and mitochondrial depolarization and on expressions of Drp1, parkin, PINK1, and LC3 were investigated in H9c2 cells after D-galactose treatment that induced senescent-like cardiomyocytes...
2017: Oxidative Medicine and Cellular Longevity
https://www.readbyqxmd.com/read/29200204/thyroid-hormone-inhibits-lung-fibrosis-in-mice-by-improving-epithelial-mitochondrial-function
#9
Guoying Yu, Argyris Tzouvelekis, Rong Wang, Jose D Herazo-Maya, Gabriel H Ibarra, Anup Srivastava, Joao Pedro Werneck de Castro, Giuseppe DeIuliis, Farida Ahangari, Tony Woolard, Nachelle Aurelien, Rafael Arrojo E Drigo, Ye Gan, Morven Graham, Xinran Liu, Robert J Homer, Thomas S Scanlan, Praveen Mannam, Patty J Lee, Erica L Herzog, Antonio C Bianco, Naftali Kaminski
Thyroid hormone (TH) is critical for the maintenance of cellular homeostasis during stress responses, but its role in lung fibrosis is unknown. Here we found that the activity and expression of iodothyronine deiodinase 2 (DIO2), an enzyme that activates TH, were higher in lungs from patients with idiopathic pulmonary fibrosis than in control individuals and were correlated with disease severity. We also found that Dio2-knockout mice exhibited enhanced bleomycin-induced lung fibrosis. Aerosolized TH delivery increased survival and resolved fibrosis in two models of pulmonary fibrosis in mice (intratracheal bleomycin and inducible TGF-β1)...
December 4, 2017: Nature Medicine
https://www.readbyqxmd.com/read/29196503/sphingolipid-regulation-of-lung-epithelial-cell-mitophagy-and-necroptosis-during-cigarette-smoke-exposure
#10
Kenji Mizumura, Matthew J Justice, Kelly S Schweitzer, Sheila Krishnan, Irina Bronova, Evgeny V Berdyshev, Walter C Hubbard, Yael Pewzner-Jung, Anthony H Futerman, Augustine M K Choi, Irina Petrache
The mechanisms by which lung structural cells survive toxic exposures to cigarette smoke (CS) are not well defined but may involve proper disposal of damaged mitochondria by macro-autophagy (mitophagy), processes that may be influenced by pro-apoptotic ceramide (Cer) or its precursor dihydroceramide (DHC). Human lung epithelial and endothelial cells exposed to CS exhibited mitochondrial damage, signaled by phosphatase and tensin homolog-induced putative kinase 1 (PINK1) phosphorylation, autophagy, and necroptosis...
December 1, 2017: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/29187900/the-cytotoxic-effects-of-dimethyl-sulfoxide-in-mouse-preimplantation-embryos-a-mechanistic-study
#11
Min-Hee Kang, Joydeep Das, Sangiliyandi Gurunathan, Hwan-Woo Park, Hyuk Song, Chankyu Park, Jin-Hoi Kim
Rationale: Dimethyl sulfoxide (DMSO) is commonly used as a solvent for water-insoluble substances, a vehicle for drug therapy, and a cryoprotectant for cultured cells. DMSO induced embryonic defects and its mechanism of action remains unclear. The rationale is based on the assumption that DMSO supplementation should induce long-term negative effects on both pre- and post-implantation embryo development. Methods: DMSO induced oxidative stress, ER stress, autophagy, mitophagy, signaling responsible genes and proteins were determined by RT-qPCR, Western blotting, immunofluorescence, and confocal microscopy...
2017: Theranostics
https://www.readbyqxmd.com/read/29180793/activation-of-the-mitochondrial-unfolded-protein-response-promotes-longevity-and-dopamine-neuron-survival-in-parkinson-s-disease-models
#12
Jason F Cooper, Emily Machiela, Dylan J Dues, Katie K Spielbauer, Megan M Senchuk, Jeremy M Van Raamsdonk
While the pathogenesis of Parkinson's disease (PD) is incompletely understood, mitochondrial dysfunction is thought to play a crucial role in disease pathogenesis. Here, we examined the relationship between mitochondrial function and dopamine neuron dysfunction and death using C. elegans mutants for three mitochondria-related genes implicated in monogenic PD (pdr-1/PRKN, pink-1/PINK1 and djr-1.1/DJ-1). We found that pdr-1 and pink-1 mutants exhibit deficits in dopamine-dependent behaviors, but no loss of dopamine neurons, while djr-1...
November 27, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29174311/mdivi-1-alleviates-blood-brain-barrier-disruption-and-cell-death-in-experimental-traumatic-brain-injury-by-mitigating-autophagy-dysfunction-and-mitophagy-activation
#13
Chengliang Luo, Qiong Wu, Qianqian Li, Xinmu Zhang, Xiuyu Shi, Xin Wang, Luyang Tao
Dynamin-related protein 1 (Drp1) is a key regulator of mitochondrial fission. Our previous studies proved that the inhibition of Drp1 may help attenuate traumatic brain injury (TBI)-induced functional outcome and cell death through maintaining normal mitochondrial morphology and inhibiting activation of apoptosis. However, the molecular mechanisms of Drp1 after TBI remain poorly understood. In this study, we investigated the role of mitochondrial division inhibitor 1 (Mdivi-1), a small molecule inhibitor of Drp1, in underlying mechanisms of general autophagy and mitochondria autophagy (mitophagy) after experimental TBI...
November 21, 2017: International Journal of Biochemistry & Cell Biology
https://www.readbyqxmd.com/read/29172924/pink1-prkn-park2-pathway-of-mitophagy-is-activated-to-protect-against-renal-ischemia-reperfusion-injury
#14
Chengyuan Tang, Hailong Han, Mingjuan Yan, Shiyao Zhu, Jing Liu, Zhiwen Liu, Liyu He, Jieqiong Tan, Yu Liu, Hong Liu, Lin Sun, Shaobin Duan, Youming Peng, Fuyou Liu, Xiao-Ming Yin, Zhuohua Zhang, Zheng Dong
Damaged or dysfunctional mitochondria are toxic to the cell by producing reactive oxygen species and releasing cell death factors. Therefore, timely removal of these organelles is critical to cellular homeostasis and viability. Mitophagy is the mechanism of selective degradation of mitochondria via autophagy. The significance of mitophagy in kidney diseases, including ischemic acute kidney injury (AKI), has yet to be established, and the involved pathway of mitophagy remains poorly understood. Here, we show that mitophagy is induced in renal proximal tubular cells in both in vitro and in vivo models of ischemic AKI...
November 26, 2017: Autophagy
https://www.readbyqxmd.com/read/29169417/-overexpression-of-ppenk-reduces-myocardial-ischemia-reperfusion-injury-by-promoting-mitophagy-in-rats
#15
Yan Wang, Xiaoe Lu, Pin Zhao, Jing Jiang, Linong Yao
Objective To investigate the effect of preproenkephalin-minimalistic immunologically defined gene expression-nuclear localization signal (PPENK-MIDGE-NLS) vector postconditioning on mitophagy during myocardial ischemia reperfusion in rats. Methods Forty male SD rats were randomly divided into 4 groups: sham operation group, ischemia reperfusion group, PPENK-MIDGE-NLS group and Control-MIDGE-NLS group. Myocardial ischemia reperfusion injury model was induced by ligating left anterior descending branch of coronary artery (LAD)...
October 2017: Xi Bao Yu Fen Zi Mian Yi Xue za Zhi, Chinese Journal of Cellular and Molecular Immunology
https://www.readbyqxmd.com/read/29166608/s-nitrosylation-of-pink1-attenuates-pink1-parkin-dependent-mitophagy-in-hipsc-based-parkinson-s-disease-models
#16
Chang-Ki Oh, Abdullah Sultan, Joseph Platzer, Nima Dolatabadi, Frank Soldner, Daniel B McClatchy, Jolene K Diedrich, John R Yates, Rajesh Ambasudhan, Tomohiro Nakamura, Rudolf Jaenisch, Stuart A Lipton
Mutations in PARK6 (PINK1) and PARK2 (Parkin) are linked to rare familial cases of Parkinson's disease (PD). Mutations in these genes result in pathological dysregulation of mitophagy, contributing to neurodegeneration. Here, we report that environmental factors causing a specific posttranslational modification on PINK1 can mimic these genetic mutations. We describe a molecular mechanism for impairment of mitophagy via formation of S-nitrosylated PINK1 (SNO-PINK1). Mitochondrial insults simulating age- or environmental-related stress lead to increased SNO-PINK1, inhibiting its kinase activity...
November 21, 2017: Cell Reports
https://www.readbyqxmd.com/read/29165030/in-mammalian-skeletal-muscle-phosphorylation-of-tomm22-by-protein-kinase-csnk2-ck2-controls-mitophagy
#17
Bojana Kravic, Angelika B Harbauer, Vanina Romanello, Luca Simeone, F-Nora Vögtle, Tobias Kaiser, Marion Straubinger, Danyil Huraskin, Martin Böttcher, Cristina Cerqua, Eva Denise Martin, Daniel Poveda-Huertes, Andreas Buttgereit, Adam J Rabalski, Dieter Heuss, Rüdiger Rudolf, Oliver Friedrich, David Litchfield, Michael Marber, Leonardo Salviati, Dimitrios Mougiakakos, Winfried Neuhuber, Marco Sandri, Chris Meisinger, Said Hashemolhosseini
In yeast, Tom22 the central component of the TOMM (translocase of outer mitochondrial membrane) receptor complex is responsible for the recognition and translocation of synthesized mitochondrial precursor proteins, and its protein kinase CK2-dependent phosphorylation is mandatory for TOMM complex biogenesis and proper mitochondrial protein import. In mammals, the biological function of protein kinase CSNK2/CK2 remains vastly elusive and it is unknown whether CSNK2-dependent phosphorylation of TOMM protein subunits has a similar role as that in yeast...
November 22, 2017: Autophagy
https://www.readbyqxmd.com/read/29163333/mutation-analysis-of-consanguineous-moroccan-patients-with-parkinson-s-disease-combining-microarray-and-gene-panel
#18
Ahmed Bouhouche, Christelle Tesson, Wafaa Regragui, Mounia Rahmani, Valérie Drouet, Houyam Tibar, Zouhayr Souirti, Rafiqua Ben El Haj, Naima Bouslam, Mohamed Yahyaoui, Alexis Brice, Ali Benomar, Suzanne Lesage
During the last two decades, 15 different genes have been reported to be responsible for the monogenic form of Parkinson's disease (PD), representing a worldwide frequency of 5-10%. Among them, 10 genes have been associated with autosomal recessive PD, with PRKN and PINK1 being the most frequent. In a cohort of 145 unrelated Moroccan PD patients enrolled since 2013, 19 patients were born from a consanguineous marriage, of which 15 were isolated cases and 4 familial. One patient was homozygous for the common LRRK2 G2019S mutation and the 18 others who did not carry this mutation were screened for exon rearrangements in the PRKN gene using Affymetrix Cytoscan HD microarray...
2017: Frontiers in Neurology
https://www.readbyqxmd.com/read/29160309/structure-of-pink1-in-complex-with-its-substrate-ubiquitin
#19
Alexander F Schubert, Christina Gladkova, Els Pardon, Jane L Wagstaff, Stefan M V Freund, Jan Steyaert, Sarah L Maslen, David Komander
Autosomal recessive juvenile Parkinsonism (AR-JP) is caused by mutations in a number of PARK genes, in particular in the E3 ubiquitin ligase Parkin (PARK2), and in its upstream protein kinase PINK1 (PARK6). PINK1 phosphorylates ubiquitin and the Parkin ubiquitin-like domain on structurally protected Ser65 to trigger mitophagy. We here report a crystal structure of a nanobody-stabilised complex between Pediculus humanus corporis (Ph)PINK1 with ubiquitin in the 'C-terminally retracted' (Ub-CR) conformation. The structure reveals many peculiarities of PINK1, including the architecture of the C-terminal region, and reveals how the PINK1 N-lobe binds ubiquitin via a unique insertion...
October 30, 2017: Nature
https://www.readbyqxmd.com/read/29156651/specific-effects-of-chronic-dietary-exposure-to-chlorpyrifos-on-brain-gene-expression-a-mouse-study
#20
Maria Michela Pallotta, Raffaele Ronca, Rosa Carotenuto, Immacolata Porreca, Mimmo Turano, Concetta Ambrosino, Teresa Capriglione
chlorpyrifos (CPF) is an organophosphate insecticide used to control pests on a variety of food and feed crops. In mammals, maternal exposure to CPF has been reported to induce cerebral cortex thinning, alteration of long-term brain cognitive function, and Parkinson-like symptoms, but the mechanisms of these processes are not fully understood. In this study, we aimed to gain a deeper understanding of the alterations induced in the brains of mice chronically exposed to CPF by dietary intake. For our purpose, we analysed F1 offspring (sacrificed at 3 and 8 months) of Mus musculus, treated in utero and postnatally with 3 different doses of CPF (0...
November 20, 2017: International Journal of Molecular Sciences
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