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https://www.readbyqxmd.com/read/27911343/pink1-parkin-and-mitochondrial-quality-control-what-can-we-learn-about-parkinson-s-disease-pathobiology
#1
Dominika Truban, Xu Hou, Thomas R Caulfield, Fabienne C Fiesel, Wolfdieter Springer
The first clinical description of Parkinson's disease (PD) will embrace its two century anniversary in 2017. For the past 30 years, mitochondrial dysfunction has been hypothesized to play a central role in the pathobiology of this devastating neurodegenerative disease. The identifications of mutations in genes encoding PINK1 (PTEN-induced kinase 1) and Parkin (E3 ubiquitin ligase) in familial PD and their functional association with mitochondrial quality control provided further support to this hypothesis. Recent research focused mainly on their key involvement in the clearance of damaged mitochondria, a process known as mitophagy...
November 30, 2016: Journal of Parkinson's Disease
https://www.readbyqxmd.com/read/27907896/harnessing-human-adar2-for-rna-repair-recoding-a-pink1-mutation-rescues-mitophagy
#2
Jacqueline Wettengel, Philipp Reautschnig, Sven Geisler, Philipp J Kahle, Thorsten Stafforst
Site-directed A-to-I RNA editing is a technology for re-programming genetic information at the RNA-level. We describe here the first design of genetically encodable guideRNAs that enable the re-addressing of human ADAR2 toward specific sites in user-defined mRNA targets. Up to 65% editing yield has been achieved in cell culture for the recoding of a premature Stop codon (UAG) into tryptophan (UIG). In the targeted gene, editing was very specific. We applied the technology to recode a recessive loss-of-function mutation in PINK1 (W437X) in HeLa cells and showed functional rescue of PINK1/Parkin-mediated mitophagy, which is linked to the etiology of Parkinson's disease...
October 7, 2016: Nucleic Acids Research
https://www.readbyqxmd.com/read/27906179/pink1-dependent-phosphorylation-of-pink1-and-parkin-is-essential-for-mitochondrial-quality-control
#3
Na Zhuang, Lin Li, She Chen, Tao Wang
Mitochondrial dysfunction has been linked to the pathogenesis of a large number of inherited diseases in humans, including Parkinson's disease, the second most common neurodegenerative disorder. The Parkinson's disease genes pink1 and parkin, which encode a mitochondrially targeted protein kinase, and an E3 ubiquitin ligase, respectively, participate in a key mitochondrial quality-control pathway that eliminates damaged mitochondria. In the current study, we established an in vivo PINK1/Parkin-induced photoreceptor neuron degeneration model in Drosophila with the aim of dissecting the PINK1/Parkin pathway in detail...
December 1, 2016: Cell Death & Disease
https://www.readbyqxmd.com/read/27901103/fsh-protects-mouse-granulosa-cells-from-oxidative-damage-by-repressing-mitophagy
#4
Ming Shen, Yi Jiang, Zhiqiang Guan, Yan Cao, Shao-Chen Sun, Honglin Liu
Oxidative stress has been implicated in triggering granulosa cell (GC) death during follicular atresia. Recent studies suggested that follicle-stimulating hormone (FSH) has a pivotal role in protecting GCs from oxidative injury, although the exact mechanism remains largely unknown. Here, we report that FSH promotes GC survival by inhibiting oxidative stress-induced mitophagy. The loss of GC viability caused by oxidative stress was significantly reduced after FSH treatment, which was correlated with impaired activation of mitophagy upon oxidative stress...
November 30, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27876828/common-variants-in-the-parl-and-pink1-genes-increase-the-risk-to-leprosy-in-han-chinese-from-south-china
#5
Dong Wang, Deng-Feng Zhang, Jia-Qi Feng, Guo-Dong Li, Xiao-An Li, Xiu-Feng Yu, Heng Long, Yu-Ye Li, Yong-Gang Yao
Leprosy is a chronic infectious and neurological disease caused by Mycobacterium leprae, an unculturable pathogen with massive genomic decay and dependence on host metabolism. We hypothesized that mitochondrial genes PARL and PINK1 would confer risk to leprosy. Thirteen tag SNPs of PARL and PINK1 were analyzed in 3620 individuals with or without leprosy from China. We also sequenced the entire exons of PARL, PINK1 and PARK2 in 80 patients with a family history of leprosy by using the next generation sequencing technology (NGS)...
November 23, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27872751/novel-gene-tmem230-linked-to-parkinson-s-disease
#6
EDITORIAL
Diana A Olszewska, Conor Fearon, Tim Lynch
Mutations in six genes are known to cause Parkinson's disease (PD) (autosomal dominant: alpha-synuclein, LRRK2, VPS35 and autosomal recessive: Parkin, PINK1 and DJ1) and number of other genes are implicated. In a recent article Deng and colleagues studied a large four generation American family of European descent and linked mutations in a novel gene, transmembrane-protein 230 gene (TMEM230) with lewy body confirmed PD. The authors demonstrated that pathogenic TMEM230 variants in primary mouse neurons affected movement of synaptic vesicles suggesting that TMEM230 may slow vesicular transport...
2016: Journal of Clinical Movement Disorders
https://www.readbyqxmd.com/read/27864321/atg8-family-lc3-gabarap-proteins-are-crucial-for-autophagosome-lysosome-fusion-but-not-autophagosome-formation-during-pink1-parkin-mitophagy-and-starvation
#7
Thanh Ngoc Nguyen, Benjamin Scott Padman, Joanne Usher, Viola Oorschot, Georg Ramm, Michael Lazarou
Members of the Atg8 family of proteins are conjugated to autophagosomal membranes, where they have been proposed to drive autophagosome formation and selective sequestration of cargo. In mammals, the Atg8 family consists of six members divided into the LC3 and GABARAP subfamilies. To define Atg8 function, we used genome editing to generate knockouts of the LC3 and GABARAP subfamilies as well as all six Atg8 family members in HeLa cells. We show that Atg8s are dispensable for autophagosome formation and selective engulfment of mitochondria, but essential for autophagosome-lysosome fusion...
November 18, 2016: Journal of Cell Biology
https://www.readbyqxmd.com/read/27859782/inhibition-of-the-mitochondrial-calcium-uniporter-mcu-rescues-dopaminergic-neurons-in-pink1-zebrafish
#8
Smijin Soman, Marcus Keatinge, Mahsa Moein, Marc DaCosta, Heather Mortiboys, Alexander Skupin, Sreedevi Sugunan, Michal Bazala, Jacek Kuznicki, Oliver Bandmann
Mutations in PTEN-induced putative kinase 1 (PINK1) are a cause of early onset Parkinson's disease (PD). Loss of PINK1 function causes dysregulation of mitochondrial calcium homeostasis, resulting in mitochondrial dysfunction and neuronal cell death. We report that both genetic and pharmacological inactivation of the mitochondrial calcium uniporter (MCU), located in the inner mitochondrial membrane, prevents dopaminergic neuronal cell loss in pink1(Y431) * mutant zebrafish (Danio rerio) via rescue of mitochondrial respiratory chain function...
November 12, 2016: European Journal of Neuroscience
https://www.readbyqxmd.com/read/27855364/parthenolide-induces-reactive-oxygen-species-mediated-autophagic-cell-death-in-human-osteosarcoma-cells
#9
Chen Yang, Qing Ou Yang, Qing-Jie Kong, Wen Yuan, Yue-Ping Ou Yang
BACKGROUND AND AIM: Osteosarcoma is a devastating tumor of bone, primarily affecting adolescents. Parthenolide, a naturally occurring small molecule that interferes with NF-κB signaling, has recently attracted considerable attention because of its pharmacological action involving anti-cancer effects. However, the mechanism of the cytotoxic effect exerted by parthenolide on tumor cells is not clearly defined today. METHODS: In this study, the effects of parthenolide were evaluated and characterized in human osteosarcoma cancer cell...
2016: Cellular Physiology and Biochemistry
https://www.readbyqxmd.com/read/27853101/trifloxystrobin-induced-mitophagy-through-mitochondrial-damage-in-human-skin-keratinocytes
#10
Yoonjeong Jang, Ji-Eun Kim, Sang-Hee Jeong, Min-Kyoung Paik, Jun Sung Kim, Myung-Haing Cho
Trifloxystrobin is a strobilurin class fungicide, the mode of action of which is to block the mitochondrial electron transport chain and inhibit energy production in fungi. Although adverse effects have been reported by occupational or environmental exposure of fungicides, the pathophysiological mechanism in human cells remains poorly understood. In the present study, we investigated the impact of trifloxystrobin on exposed skin at the cellular organelle level using HaCaT, the human skin keratinocyte cell line...
2016: Journal of Toxicological Sciences
https://www.readbyqxmd.com/read/27852436/elimination-of-paternal-mitochondria-in-mouse-embryos-occurs-through-autophagic-degradation-dependent-on-parkin-and-mul1
#11
Rebecca Rojansky, Moon-Yong Cha, David C Chan
A defining feature of mitochondria is their maternal mode of inheritance. However, little is understood about the cellular mechanism through which paternal mitochondria, delivered from sperm, are eliminated from early mammalian embryos. Autophagy has been implicated in nematodes, but whether this mechanism is conserved in mammals has been disputed. Here, we show that cultured mouse fibroblasts and pre-implantation embryos use a common pathway for elimination of mitochondria. Both situations utilize mitophagy, in which mitochondria are sequestered by autophagosomes and delivered to lysosomes for degradation...
November 17, 2016: ELife
https://www.readbyqxmd.com/read/27846363/phospho-ubiquitin-park2-complex-as-a-marker-for-mitophagy-defects
#12
Sylvie Callegari, Silke Oeljeklaus, Bettina Warscheid, Sven Dennerlein, Michael Thumm, Peter Rehling, Jan Dudek
The E3 ubiquitin ligase PARK2 and the mitochondrial protein kinase PINK1 are required for the initiation of mitochondrial damage-induced mitophagy. Together, PARK2 and PINK1 generate a phospho-ubiquitin signal on outer mitochondrial membrane proteins that triggers recruitment of the autophagy machinery. This paper describes the detection of a defined 500-kDa phospho-ubiquitin-rich PARK2 complex that accumulates on mitochondria upon treatment with the membrane uncoupler CCCP. Formation of this complex is dependent on the presence of PINK1 and is absent in mutant forms of PARK2, whereby mitophagy is also arrested...
November 15, 2016: Autophagy
https://www.readbyqxmd.com/read/27843055/abnormal-premotor-motor-interaction-in-heterozygous-parkin-and-pink1-mutation-carriers
#13
Anne Weissbach, Tobias Bäumer, Peter P Pramstaller, Norbert Brüggemann, Vera Tadic, Robert Chen, Christine Klein, Alexander Münchau
OBJECTIVES: Mutations in the Parkin and PINK1 gene account for the majority of autosomal recessive early-onset Parkinson cases. There is increasing evidence that clinically asymptomatic subjects with single heterozygous mutations have a latent nigrostriatal dopaminergic deficit and could be taken as in vivo model of pre-symptomatic phase of Parkinsonism. METHODS: We charted premotor-motor excitability changes as compensatory mechanisms for subcortical dopamine depletions using transcranial magnetic stimulation by applying magnetic resonance-navigated premotor-motor cortex conditioning in 15 asymptomatic, heterozygous Parkin and PINK1 mutation carriers (2 female; mean age 53±8years) and 16 age- and sex-matched controls (5 female; mean age 57±9years)...
October 26, 2016: Clinical Neurophysiology: Official Journal of the International Federation of Clinical Neurophysiology
https://www.readbyqxmd.com/read/27819722/identifying-potential-paris-homologs-in-d-melanogaster
#14
E M Merzetti, B E Staveley
Mitochondrial destruction leads to the formation of reactive oxygen species, increases cellular stress, causes apoptotic cell death, and involves a cascade of proteins including PARKIN, PINK1, and Mitofusin2. Mitochondrial biogenesis pathways depend upon the activity of the protein PGC-1α. These two processes are coordinated by the activity of a transcriptional repressor, Parkin interacting substrate (PARIS). The PARIS protein is degraded through the activity of the PARKIN protein, which in turn eliminates the transcriptional repression that PARIS imposes upon a downstream target, PGC-1α...
November 3, 2016: Genetics and Molecular Research: GMR
https://www.readbyqxmd.com/read/27818248/genetics-of-parkinson-s-disease
#15
REVIEW
Christina M Lill
Almost two decades after the identification of SNCA as the first causative gene in Parkinson's disease (PD) and the subsequent understanding that genetic factors play a substantial role in PD development, our knowledge of the genetic architecture underlying this disease has vastly improved. Approximately 5-10% of patients suffer from a monogenic form of PD where autosomal dominant mutations in SNCA, LRRK2, and VPS35 and autosomal recessive mutations in PINK1, DJ-1, and Parkin cause the disease with high penetrance...
December 2016: Molecular and Cellular Probes
https://www.readbyqxmd.com/read/27813658/recql4-regulates-autophagy-and-apoptosis-in-u2os-cells
#16
Yangmiao Duan, Hongbo Fang
RecQL4, one of the 5 human RecQ helicases, is a key mediator of genomic stability and its deficiency can cause premature aging phenotypes. Here, by using CRISPR/Cas and RNAi technology, we demonstrated that autophagy level was elevated in both RecQL4 knockdown and knockout cells compared with those of the control cells. Surprisingly, mitochondrial content was increased and LC3 co-localization with mitochondria was partially lost in RecQL4 knockout cells compared with the control cells, suggesting that RecQL4 deficiency impaired mitophagic processes in U2OS cells...
December 2016: Biochemistry and Cell Biology, Biochimie et Biologie Cellulaire
https://www.readbyqxmd.com/read/27807159/seeking-an-in-vivo-neuronal-context-for-the-pink1-parkin-pathway
#17
Nicholas R Ader
No abstract text is available yet for this article.
November 2, 2016: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/27807026/heterozygous-pink1-p-g411s-increases-risk-of-parkinson-s-disease-via-a-dominant-negative-mechanism
#18
Andreas Puschmann, Fabienne C Fiesel, Thomas R Caulfield, Roman Hudec, Maya Ando, Dominika Truban, Xu Hou, Kotaro Ogaki, Michael G Heckman, Elle D James, Maria Swanberg, Itzia Jimenez-Ferrer, Oskar Hansson, Grzegorz Opala, Joanna Siuda, Magdalena Boczarska-Jedynak, Andrzej Friedman, Dariusz Koziorowski, Jan O Aasly, Timothy Lynch, George D Mellick, Megha Mohan, Peter A Silburn, Yanosh Sanotsky, Carles Vilariño-Güell, Matthew J Farrer, Li Chen, Valina L Dawson, Ted M Dawson, Zbigniew K Wszolek, Owen A Ross, Wolfdieter Springer
It has been postulated that heterozygous mutations in recessive Parkinson's genes may increase the risk of developing the disease. In particular, the PTEN-induced putative kinase 1 (PINK1) p.G411S (c.1231G>A, rs45478900) mutation has been reported in families with dominant inheritance patterns of Parkinson's disease, suggesting that it might confer a sizeable disease risk when present on only one allele. We examined families with PINK1 p.G411S and conducted a genetic association study with 2560 patients with Parkinson's disease and 2145 control subjects...
November 2, 2016: Brain: a Journal of Neurology
https://www.readbyqxmd.com/read/27802836/involvement-of-heat-shock-proteins-on-mn-induced-toxicity-in-caenorhabditis-elegans
#19
Daiana Silva Avila, Alexandre Benedetto, Catherine Au, Julia Bornhorst, Michael Aschner
BACKGROUND: All living cells display a rapid molecular response to adverse environmental conditions, and the heat shock protein family reflects one such example. Hence, failing to activate heat shock proteins can impair the cellular response. In the present study, we evaluated whether the loss of different isoforms of heat shock protein (hsp) genes in Caenorhabditis elegans would affect their vulnerability to Manganese (Mn) toxicity. METHODS: We exposed wild type and selected hsp mutant worms to Mn (30 min) and next evaluated further the most susceptible strains...
November 2, 2016: BMC Pharmacology & Toxicology
https://www.readbyqxmd.com/read/27794540/pink1-and-parkin-are-genetic-modifiers-for-fus-induced-neurodegeneration
#20
Yanbo Chen, Jianwen Deng, Peng Wang, Mengxue Yang, Xiaoping Chen, Li Zhu, Jianghong Liu, Bingwei Lu, Yan Shen, Kazuo Fushimi, Qi Xu, Jane Y Wu
Dysregulation of FUS gene expression is associated with fronto-temporal lobar degeneration (FTLD), and missense mutations in the FUS gene have been identified in patients affected by amyotrophic lateral sclerosis (ALS). However, molecular and cellular defects underlying FUS proteinopathy remain to be elucidated. Here, we examined whether genes important for mitochondrial quality control play a role in FUS proteinopathy. In our genetic screening, Pink1 and Park genes were identified as modifiers of neurodegeneration phenotypes induced by wild type (Wt) or ALS-associated P525L-mutant human FUS...
October 29, 2016: Human Molecular Genetics
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