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https://www.readbyqxmd.com/read/28106473/overexpression-of-buffy-enhances-the-loss-of-parkin-and-suppresses-the-loss-of-pink1-phenotypes-in-drosophila
#1
P Githure M'Angale, Brian E Staveley
Mutations in parkin (PARK2) and Pink1 (PARK6) are responsible for autosomal recessive forms of early onset Parkinson's disease (PD). Attributed to the failure of neurons to clear dysfunctional mitochondria, loss of gene expression leads to loss of nigrostriatal neurons. The Pink1/parkin pathway plays a role in the quality control mechanism aimed at eliminating defective mitochondria, and the failure of this mechanism results in a reduced lifespan and impaired locomotor ability, among other phenotypes. Inhibition of parkin or Pink1 through the induction of stable RNAi transgene in the Ddc-Gal4-expressing neurons results in such phenotypes to model PD...
December 22, 2016: Genome Génome / Conseil National de Recherches Canada
https://www.readbyqxmd.com/read/28063983/loss-of-laforin-or-malin-results-in-increased-drp1-level-and-concomitant-mitochondrial-fragmentation-in-lafora-disease-mouse-models
#2
Mamta Upadhyay, Saloni Agarwal, Pratibha Bhadauriya, Subramaniam Ganesh
Lafora disease (LD) is an autosomal recessive form of a fatal disorder characterized by the myoclonus epilepsy, ataxia, psychosis, dementia, and dysarthria. A hallmark of LD is the presence of abnormal glycogen inclusions called Lafora bodies in the affected tissues including the neurons. LD can be caused by defects either in the laforin phosphatase coded by the EPM2A gene or in the malin E3 ubiquitin ligase coded by the NHLRC1 gene. The mouse models of LD, created by the targeted disruption of the LD genes, display several neurodegenerative changes...
January 4, 2017: Neurobiology of Disease
https://www.readbyqxmd.com/read/28055010/continued-26s-proteasome-dysfunction-in-mouse-brain-cortical-neurons-impairs-autophagy-and-the-keap1-nrf2-oxidative-defence-pathway
#3
Aslihan Ugun-Klusek, Michael H Tatham, Jamal Elkharaz, Dumitru Constantin-Teodosiu, Karen Lawler, Hala Mohamed, Simon M L Paine, Glen Anderson, R John Mayer, James Lowe, E Ellen Billett, Lynn Bedford
The ubiquitin-proteasome system (UPS) and macroautophagy (autophagy) are central to normal proteostasis and interdependent in that autophagy is known to compensate for the UPS to alleviate ensuing proteotoxic stress that impairs cell function. UPS and autophagy dysfunctions are believed to have a major role in the pathomechanisms of neurodegenerative disease. Here we show that continued 26S proteasome dysfunction in mouse brain cortical neurons causes paranuclear accumulation of fragmented dysfunctional mitochondria, associated with earlier recruitment of Parkin and lysine 48-linked ubiquitination of mitochondrial outer membrane (MOM) proteins, including Mitofusin-2...
January 5, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28045767/autophagy-in-hepatocytes-in-infants-with-alpha-1-atd-and-different-liver-disease-outcomes-a-retrospective-analysis
#4
Elżbieta Czarnowska, Agnieszka Bakuła, Joanna B Bierła, Justyna Niderla-Bielińska, Agnieszka Sowińska, Joanna Cielecka-Kuszyk, Piotr Socha
OBJECTIVES: It is unclear whether a distinct activity of pathways removing the AT protein in Alpha-1-Antitrypsin Deficiency (α1ATD) are associated with an unfavorable predisposition toliver disease in the future. The aim of this study was to determine whether liverspecific activity of AT protein disposal occurs at infancy in α1ATD with PiZZ phenotype (ATZ). METHODS: Liver samples of 17 infants with unfavorable ATZ outcome (Group I, n = 8, median age  = 0...
December 30, 2016: Journal of Pediatric Gastroenterology and Nutrition
https://www.readbyqxmd.com/read/28042771/oxidative-stress-pro-inflammatory-cytokines-and-antioxidants-regulate-expression-levels-of-micrornas-in-parkinson-s-disease
#5
Kedar N Prasad
Parkinson's disease (PD) is a slow progressive neurodegenerative disease associated with abnormal function of extrapyramidal system. Although several biochemical and genetic defects have been identified, increased oxidative stress and chronic inflammation are one of the earliest events that initiate and promote PD. Oxidative stress also participates in impaired non-motor symptoms.The levels of microRNAs that are evolutionarily conserved single-stranded non-coding RNAs of approximately 22 nucleotide in length are altered in PD...
January 2, 2017: Current Aging Science
https://www.readbyqxmd.com/read/28017782/parkin-and-pink1-functions-in-oxidative-stress-and-neurodegeneration
#6
Sandeep K Barodia, Rose B Creed, Matthew S Goldberg
Loss-of-function mutations in the genes encoding Parkin and PINK1 are causally linked to autosomal recessive Parkinson's disease (PD). Parkin, an E3 ubiquitin ligase, and PINK1, a mitochondrial-targeted kinase, function together in a common pathway to remove dysfunctional mitochondria by autophagy. Presumably, deficiency for Parkin or PINK1 impairs mitochondrial autophagy and thereby increases oxidative stress due to the accumulation of dysfunctional mitochondria that release reactive oxygen species. Parkin and PINK1 likely have additional functions that may be relevant to the mechanisms by which mutations in these genes cause neurodegeneration, such as regulating inflammation, apoptosis, or dendritic morphogenesis...
December 22, 2016: Brain Research Bulletin
https://www.readbyqxmd.com/read/28007983/structure-of-phosphorylated-ubl-domain-and-insights-into-pink1-orchestrated-parkin-activation
#7
Jacob D Aguirre, Karen M Dunkerley, Pascal Mercier, Gary S Shaw
Mutations in PARK2 and PARK6 genes are responsible for the majority of hereditary Parkinson's disease cases. These genes encode the E3 ubiquitin ligase parkin and the protein kinase PTEN-induced kinase 1 (PINK1), respectively. Together, parkin and PINK1 regulate the mitophagy pathway, which recycles damaged mitochondria following oxidative stress. Native parkin is inactive and exists in an autoinhibited state mediated by its ubiquitin-like (UBL) domain. PINK1 phosphorylation of serine 65 in parkin's UBL and serine 65 of ubiquitin fully activate ubiquitin ligase activity; however, a structural rationale for these observations is not clear...
December 22, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27926857/a-lon-clpp-proteolytic-axis-degrades-complex-i-to-extinguish-ros-production-in-depolarized-mitochondria
#8
Kenneth Robert Pryde, Jan Willem Taanman, Anthony Henry Schapira
Mitochondrial dysfunction is implicated in numerous neurodegenerative disorders and in Parkinson's disease (PD) in particular. PINK1 and Parkin gene mutations are causes of autosomal recessive PD, and these respective proteins function cooperatively to degrade depolarized mitochondria (mitophagy). It is widely assumed that impaired mitophagy causes PD, as toxic reactive oxygen species (ROS)-producing mitochondria accumulate and progressively drive neurodegeneration. Instead, we report that a LON-ClpP proteolytic quality control axis extinguishes ROS in depolarized mitochondria by degrading the complex I ROS-generating domain...
December 6, 2016: Cell Reports
https://www.readbyqxmd.com/read/27925791/reemergence-of-lower-airway-microbiota-in-lung-transplant-patients-with-cystic-fibrosis
#9
Saad A Syed, Fiona J Whelan, Barbara Waddell, Harvey R Rabin, Michael D Parkins, Michael G Surette
RATIONALE: Chronic lung infections are a hallmark of cystic fibrosis; they are responsible for progressive airway destruction and ultimately lead to respiratory death or the requirement for life-saving bilateral lung transplant. Furthermore, recurrent isolation of airway pathogens such as Pseudomonas aeruginosa in the allograft after transplant is associated with adverse outcomes, including bronchiolitis obliterans syndrome and acute infections. Little information exists on the impact of bilateral lung transplant on the lower-airway microbiota...
December 2016: Annals of the American Thoracic Society
https://www.readbyqxmd.com/read/27911343/pink1-parkin-and-mitochondrial-quality-control-what-can-we-learn-about-parkinson-s-disease-pathobiology
#10
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
#11
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
#12
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/27903732/parkin-deficiency-reduces-hippocampal-glutamatergic-neurotransmission-by-impairing-ampa-receptor-endocytosis
#13
Giuseppe P Cortese, Mei Zhu, Damian Williams, Sarah Heath, Clarissa L Waites
: Mutations in the gene encoding Parkin, an E3 ubiquitin ligase, lead to juvenile-onset Parkinson's disease by inducing the selective death of midbrain dopaminergic neurons. Accumulating evidence indicates that Parkin also has an important role in excitatory glutamatergic neurotransmission, although its precise mechanism of action remains unclear. Here, we investigate Parkin's role at glutamatergic synapses of rat hippocampal neurons. We find that Parkin-deficient neurons exhibit significantly reduced AMPA receptor (AMPAR)-mediated currents and cell-surface expression, and that these phenotypes result from decreased postsynaptic expression of the adaptor protein Homer1, which is necessary for coupling AMPAR endocytic zones with the postsynaptic density...
November 30, 2016: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/27872751/novel-gene-tmem230-linked-to-parkinson-s-disease
#14
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/27855364/parthenolide-induces-reactive-oxygen-species-mediated-autophagic-cell-death-in-human-osteosarcoma-cells
#15
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/27843055/abnormal-premotor-motor-interaction-in-heterozygous-parkin-and-pink1-mutation-carriers
#16
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)...
January 2017: Clinical Neurophysiology: Official Journal of the International Federation of Clinical Neurophysiology
https://www.readbyqxmd.com/read/27834372/the-pangenome-of-an-agronomically-important-crop-plant-brassica-oleracea
#17
Agnieszka A Golicz, Philipp E Bayer, Guy C Barker, Patrick P Edger, HyeRan Kim, Paula A Martinez, Chon Kit Kenneth Chan, Anita Severn-Ellis, W Richard McCombie, Isobel A P Parkin, Andrew H Paterson, J Chris Pires, Andrew G Sharpe, Haibao Tang, Graham R Teakle, Christopher D Town, Jacqueline Batley, David Edwards
There is an increasing awareness that as a result of structural variation, a reference sequence representing a genome of a single individual is unable to capture all of the gene repertoire found in the species. A large number of genes affected by presence/absence and copy number variation suggest that it may contribute to phenotypic and agronomic trait diversity. Here we show by analysis of the Brassica oleracea pangenome that nearly 20% of genes are affected by presence/absence variation. Several genes displaying presence/absence variation are annotated with functions related to major agronomic traits, including disease resistance, flowering time, glucosinolate metabolism and vitamin biosynthesis...
November 11, 2016: Nature Communications
https://www.readbyqxmd.com/read/27824727/definition-of-a-putative-pathological-region-in-park2-associated-with-autism-spectrum-disorder-through-insilico-analysis-of-its-functional-structure
#18
Inês C Conceição, Maria M Rama, Bárbara Oliveira, Cátia Café, Joana Almeida, Susana Mouga, Frederico Duque, Guiomar Oliveira, Astrid M Vicente
OBJECTIVE: The PARK2 gene encodes Parkin, a component of a multiprotein E3 ubiquitin ligase complex that targets substrate proteins for proteasomal degradation. PARK2 mutations are frequently associated with Parkinson's disease, but structural alterations have also been described in patients with neurodevelopmental disorders (NDD), suggesting a pathological effect ubiquitous to neurodevelopmental and neurodegenerative brain processes. The present study aimed to define the critical regions for NDD within PARK2...
November 7, 2016: Psychiatric Genetics
https://www.readbyqxmd.com/read/27819722/identifying-potential-paris-homologs-in-d-melanogaster
#19
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
#20
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
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