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https://www.readbyqxmd.com/read/28222786/post-translational-modification-of-parkin
#1
REVIEW
Joy Chakraborty, Valentina Basso, Elena Ziviani
: Mutations in the gene encoding for the E3 ubiquitin ligase Parkin are associated to a rare form of familiar autosomal recessive Parkinsonism. Despite decades of research on the Parkin protein, whose structure has been recently solved, little is known about the specific signalling pathways that lead to Parkin activation. Parkin activity spans from mitochondria quality control to tumor suppression and stress protection; it is thus tempting to hypothesize that the broad impact of Parkin on cellular physiology might be the result of different post translational modifications that can be controlled by balanced opposing events...
February 21, 2017: Biology Direct
https://www.readbyqxmd.com/read/28222538/vps35-the-retromer-complex-and-parkinson-s-disease
#2
Erin T Williams, Xi Chen, Darren J Moore
Mutations in the vacuolar protein sorting 35 ortholog (VPS35) gene encoding a core component of the retromer complex, have recently emerged as a new cause of late-onset, autosomal dominant familial Parkinson's disease (PD). A single missense mutation, AspD620Asn (D620N), has so far been unambiguously identified to cause PD in multiple individuals and families worldwide. The exact molecular mechanism(s) by which VPS35 mutations induce progressive neurodegeneration in PD are not yet known. Understanding these mechanisms, as well as the perturbed cellular pathways downstream of mutant VPS35, is important for the development of appropriate therapeutic strategies...
February 8, 2017: Journal of Parkinson's Disease
https://www.readbyqxmd.com/read/28213158/pink1-parkin-mitophagy-and-neurodegeneration-what-do-we-really-know-in-vivo
#3
REVIEW
Alexander J Whitworth, Leo J Pallanck
Mitochondria are essential organelles that provide cellular energy and buffer cytoplasmic calcium. At the same time they produce damaging reactive oxygen species and sequester pro-apoptotic factors. Hence, eukaryotes have evolved exquisite homeostatic processes that maintain mitochondrial integrity, or ultimately remove damaged organelles. This subject has garnered intense interest recently following the discovery that two Parkinson's disease genes, PINK1 and parkin, regulate mitochondrial degradation (mitophagy)...
February 14, 2017: Current Opinion in Genetics & Development
https://www.readbyqxmd.com/read/28213071/pla2g6-accumulates-in-lewy-bodies-in-park14-and-idiopathic-parkinson-s-disease
#4
Yasuo Miki, Kunikazu Tanji, Fumiaki Mori, Akiyoshi Kakita, Hitoshi Takahashi, Koichi Wakabayashi
The histopathological hallmark of Parkinson's disease (PD) and dementia with Lewy bodies (DLB) is the occurrence of insoluble fibrillary aggregates known as Lewy bodies, in which phosphorylated α-synuclein (α-syn) is a major component. To date, familial PD-linked gene products, including α-syn, parkin, PINK-1, DJ-1 and LRRK2, are known to be involved in Lewy body formation. Phospholipase A2, group VI (PLA2G6) is the causative gene for PARK14-linked parkinsonism (PARK14), a familial form of juvenile-onset dystonia parkinsonism...
February 14, 2017: Neuroscience Letters
https://www.readbyqxmd.com/read/28211874/datf4-regulation-of-mitochondrial-folate-mediated-one-carbon-metabolism-is-neuroprotective
#5
Ivana Celardo, Susann Lehmann, Ana C Costa, Samantha Hy Loh, L Miguel Martins
Neurons rely on mitochondria as their preferred source of energy. Mutations in PINK1 and PARKIN cause neuronal death in early-onset Parkinson's disease (PD), thought to be due to mitochondrial dysfunction. In Drosophila pink1 and parkin mutants, mitochondrial defects lead to the compensatory upregulation of the mitochondrial one-carbon cycle metabolism genes by an unknown mechanism. Here we uncover that this branch is triggered by the activating transcription factor 4 (ATF4). We show that ATF4 regulates the expression of one-carbon metabolism genes SHMT2 and NMDMC as a protective response to mitochondrial toxicity...
February 17, 2017: Cell Death and Differentiation
https://www.readbyqxmd.com/read/28205494/language-deficits-as-a-preclinical-window-into-parkinson-s-disease-evidence-from-asymptomatic-parkin-and-dardarin-mutation-carriers
#6
Adolfo M García, Lucas Sedeño, Natalia Trujillo, Yamile Bocanegra, Diana Gomez, David Pineda, Andrés Villegas, Edinson Muñoz, William Arias, Agustín Ibáñez
OBJECTIVES: The worldwide spread of Parkinson's disease (PD) calls for sensitive and specific measures enabling its early (or, ideally, preclinical) detection. Here, we use language measures revealing deficits in PD to explore whether similar disturbances are present in asymptomatic individuals at risk for the disease. METHODS: We administered executive, semantic, verb-production, and syntactic tasks to sporadic PD patients, genetic PD patients with PARK2 (parkin) or LRRK2 (dardarin) mutation, asymptomatic first-degree relatives of the latter with similar mutations, and socio-demographically matched controls...
February 2017: Journal of the International Neuropsychological Society: JINS
https://www.readbyqxmd.com/read/28171547/cystic-fibrosis-gene-modifier-slc26a9-modulates-airway-response-to-cftr-directed-therapeutics
#7
Lisa J Strug, Tanja Gonska, Gengming He, Katherine Keenan, Wan Ip, Pierre-Yves Boëlle, Fan Lin, Naim Panjwani, Jiafen Gong, Weili Li, David Soave, Bowei Xiao, Elizabeth Tullis, Harvey Rabin, Michael D Parkins, April Price, Peter C Zuberbuhler, Harriet Corvol, Felix Ratjen, Lei Sun, Christine E Bear, Johanna M Rommens
No abstract text is available yet for this article.
October 15, 2016: Human Molecular Genetics
https://www.readbyqxmd.com/read/28169962/parkin-mediates-neuroprotection-through-activation-of-notch1-signaling
#8
Ji-Hye Yoon, Eun-Jung Ann, Mi-Yeon Kim, Ji-Seon Ahn, Eun-Hye Jo, Hye-Jin Lee, Hye-Won Lee, Young Chul Lee, Jeong-Sun Kim, Hee-Sae Park
Parkin, an E3 ubiquitin ligase, is the most frequently mutated gene in hereditary Parkinson's disease. Inactivation of Parkin leads to impairment of the ubiquitin-proteasome system, resulting in the accumulation of misfolded or aggregated proteins and ensuing neurodegeneration. In this study, we show that Parkin positively regulates the Notch1 signaling pathway. Overexpression of Parkin stabilized Notch1-IC protein levels, whereas knockdown of Parkin decreased Notch1-IC protein stability. Notably, overexpression of Parkin disrupted oxidative stress-induced apoptosis in neuronal cells...
February 4, 2017: Neuroreport
https://www.readbyqxmd.com/read/28165849/autophagosome-formation-and-cargo-sequestration-in-the-absence-of-lc3-gabaraps
#9
Benjamin Scott Padman, Thanh Ngoc Nguyen, Michael Lazarou
It has been widely assumed that Atg8 family LC3/GABARAP proteins are essential for the formation of autophagosomes during macroautophagy/autophagy, and the sequestration of cargo during selective autophagy. However, there is little direct evidence on the functional contribution of these proteins to autophagosome biogenesis in mammalian cells. To dissect the functions of LC3/GABARAPs during starvation-induced autophagy and PINK1-PARK2/Parkin-dependent mitophagy, we utilized CRISPR/Cas9 gene editing to generate knockouts of the LC3 and GABARAP subfamilies, and all 6 Atg8 family proteins in HeLa cells...
February 6, 2017: Autophagy
https://www.readbyqxmd.com/read/28129614/effects-of-titanium-dioxide-nanoparticles-exposure-on-parkinsonism-in-zebrafish-larvae-and-pc12
#10
Qinglian Hu, Fengliang Guo, Fenghui Zhao, Zhengwei Fu
Nanomaterials hold significant potential for industrial and biomedical application these years. Therefore, the relationship between nanoparticles and neurodegenerative disease is of enormous interest. In this contribution, zebrafish embryos and PC12 cell lines were selected for studying neurotoxicity of titanium dioxide nanoparticles (TiO2 NPs). After exposure of different concentrations of TiO2 NPs to embryos from fertilization to 96 hpf, the hatching time of zebrafish was decreased, accompanied by an increase in malformation rate...
January 16, 2017: Chemosphere
https://www.readbyqxmd.com/read/28124127/acute-low-intensity-cycling-with-blood-flow-restriction-has-no-effect-on-metabolic-signaling-in-human-skeletal-muscle-compared-to-traditional-exercise
#11
William J Smiles, Miguel S Conceição, Guilherme D Telles, Mara P T Chacon-Mikahil, Cláudia R Cavaglieri, Felipe C Vechin, Cleiton A Libardi, John A Hawley, Donny M Camera
PURPOSE: Autophagy is an intracellular degradative system sensitive to hypoxia and exercise-induced perturbations to cellular bioenergetics. We determined the effects of low-intensity endurance-based exercise performed with blood-flow restriction (BFR) on cell signaling adaptive responses regulating autophagy and substrate metabolism in human skeletal muscle. METHODS: In a randomized cross-over design, nine young, healthy but physically inactive males completed three experimental trials separated by 1 week of recovery consisting of either a resistance exercise bout (REX: 4 × 10 leg press repetitions, 70% 1-RM), endurance exercise (END: 30 min cycling, 70% VO2peak), or low-intensity cycling with BFR (15 min, 40% VO2peak)...
January 25, 2017: European Journal of Applied Physiology
https://www.readbyqxmd.com/read/28106473/overexpression-of-buffy-enhances-the-loss-of-parkin-and-suppresses-the-loss-of-pink1-phenotypes-in-drosophila
#12
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
#13
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
#14
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
#15
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
#16
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
#17
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
#18
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...
January 10, 2017: 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
#19
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
#20
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
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