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https://www.readbyqxmd.com/read/29325612/genetics-of-parkinson-disease
#1
Aloysius Domingo, Christine Klein
An understanding of the genetic etiology of Parkinson disease (PD) has become imperative for the modern-day neurologist. Although genetic forms cause only a minority of PD, the disease mechanisms they elucidate advance the understanding of idiopathic cases. Moreover, recently identified susceptibility variants contribute to complex-etiology PD and broaden the contribution of genetics beyond familial and early-onset cases. Dominantly inherited monogenic forms mimic idiopathic PD and are caused by mutations or copy number variations of SNCA, LRRK2, and VPS35...
2018: Handbook of Clinical Neurology
https://www.readbyqxmd.com/read/29311685/synaptotagmin-11-is-a-critical-mediator-of-parkin-linked-neurotoxicity-and-parkinson-s-disease-like-pathology
#2
Changhe Wang, Xinjiang Kang, Li Zhou, Zuying Chai, Qihui Wu, Rong Huang, Huadong Xu, Meiqin Hu, Xiaoxuan Sun, Suhua Sun, Jie Li, Ruiying Jiao, Panli Zuo, Lianghong Zheng, Zhenyu Yue, Zhuan Zhou
Loss-of-function mutations in Parkin are the most common causes of autosomal recessive Parkinson's disease (PD). Many putative substrates of parkin have been reported; their pathogenic roles, however, remain obscure due to poor characterization, particularly in vivo. Here, we show that synaptotagmin-11, encoded by a PD-risk gene SYT11, is a physiological substrate of parkin and plays critical roles in mediating parkin-linked neurotoxicity. Unilateral overexpression of full-length, but not C2B-truncated, synaptotagmin-11 in the substantia nigra pars compacta (SNpc) impairs ipsilateral striatal dopamine release, causes late-onset degeneration of dopaminergic neurons, and induces progressive contralateral motor abnormalities...
January 8, 2018: Nature Communications
https://www.readbyqxmd.com/read/29311479/transcriptome-analysis-reveals-that-midnolin-regulates-mrna-expression-levels-of-multiple-parkinson-s-disease-causative-genes
#3
Yutaro Obara, Kuniaki Ishii
We recently found that 10.5% of sporadic Parkinson's disease (PD) patients lacked one copy of the midnolin (MIDN) gene. In addition, gene knock-down/out of MIDN caused down-regulation of parkin E3 ubiquitin ligase, indicating MIDN to be a novel PD-risk factor or causative gene. In this study, we performed RNA-sequencing and transcriptome analysis of Midn wild-type and knockout cells. Midn positively or negatively regulated the expression of a wide variety of genes, including causative familial PD genes, such as α-synuclein, parkin, and EIF4G1...
2018: Biological & Pharmaceutical Bulletin
https://www.readbyqxmd.com/read/29285276/pilot-study-molecular-risk-factors-for-diagnosing-sporadic-parkinson-s-disease-based-on-gene-expression-in-blood-in-mptp-induced-rhesus-monkeys
#4
Liangqin Shi, Chao Huang, Qihui Luo, Yu Xia, Heng Liu, Like Li, Wentao Liu, Wenjing Ma, Jing Fang, Li Tang, Wen Zeng, Zhengli Chen
Clinical diagnosis of Parkinson's disease (PD) is characterized by the classical features of tremor, bradykinesia and rigidity, which are present only when more than 70%-80% degeneration of dopaminergic (DA) neurons in the substantia nigra. The lack of means for early diagnosis of PD has elicited interest in searching for its risk factors, which, by now, are almost obtained at a single time point in PD process, and little developing risk factors, obtained from completely normal situation to the onset or even advanced stage of PD in individual person which could monitor the progress of PD, are present...
December 1, 2017: Oncotarget
https://www.readbyqxmd.com/read/29242317/enzyme-free-nucleic-acid-dynamical-systems
#5
Niranjan Srinivas, James Parkin, Georg Seelig, Erik Winfree, David Soloveichik
Chemistries exhibiting complex dynamics-from inorganic oscillators to gene regulatory networks-have been long known but either cannot be reprogrammed at will or rely on the sophisticated enzyme chemistry underlying the central dogma. Can simpler molecular mechanisms, designed from scratch, exhibit the same range of behaviors? Abstract chemical reaction networks have been proposed as a programming language for complex dynamics, along with their systematic implementation using short synthetic DNA molecules. We developed this technology for dynamical systems by identifying critical design principles and codifying them into a compiler automating the design process...
December 15, 2017: Science
https://www.readbyqxmd.com/read/29222404/lack-of-parkin-anticipates-the-phenotype-and-affects-mitochondrial-morphology-and-mtdna-levels-in-a-mouse-model-of-parkinson-s-disease
#6
Milena Pinto, Nadee Nissanka, Carlos T Moraes
PARK2 is the most common gene mutated in monogenic recessive familial cases of Parkinson's disease (PD). Pathogenic mutations cause a loss of function of the encoded protein Parkin. ParkinKO mice, however, poorly represent human PD symptoms as they only exhibit mild motor phenotypes, minor dopamine metabolism abnormalities, and no signs of dopaminergic neurodegeneration. Parkin has been shown to participate in mitochondrial turnover, by targeting damaged mitochondria, with low membrane potential, to mitophagy...
December 8, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/29205771/homoeologous-exchange-is-a-major-cause-of-gene-presence-absence-variation-in-the-amphidiploid-brassica-napus
#7
Bhavna Hurgobin, Agnieszka A Golicz, Philipp E Bayer, Chon-Kit Kenneth Chan, Soodeh Tirnaz, Aria Dolatabadian, Sarah V Schiessl, Birgit Samans, Juan D Montenegro, Isobel A P Parkin, J Chris Pires, Boulos Chalhoub, Graham J King, Rod Snowdon, Jacqueline Batley, David Edwards
Homoeologous exchanges (HEs) have been shown to generate novel gene combinations and phenotypes in a range of polyploid species. Gene presence/absence variation (PAV) is also a major contributor to genetic diversity. In the present study we show that there is an association between these two events, particularly in recent Brassica napus synthetic accessions, and that these represent a novel source of genetic diversity, which can be captured for the improvement of this important crop species. By assembling the pangenome of B...
December 4, 2017: Plant Biotechnology Journal
https://www.readbyqxmd.com/read/29187900/the-cytotoxic-effects-of-dimethyl-sulfoxide-in-mouse-preimplantation-embryos-a-mechanistic-study
#8
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/29178074/beyond-deubiquitylation-usp30-mediated-regulation-of-mitochondrial-homeostasis
#9
Jiayun Hou, Mohmmad Eldeeb, Xiangdong Wang
Mutations or sequence aberrations in the Parkin gene are among the most common causes of autosomal recessive Parkinson's disorder (PD). Parkin, a cytoplasmic E3 ubiquitin ligase, is involved in mitochondrial quality control pathways, including mitochondrial fission and mitophagy by autophagy-related genes. Parkin mediates the covalent addition of ubiquitin (Ub) chains to Lys 6, Lys 11, and Lys 63 on diverse mitochondrial-related target proteins. USP30, a mitochondrial deubiquitinase, promotes mitochondrial fusion by mediating the deubiquitination of ubiquitylated forms of mitofusins, such as Mfn1 and Mfn2...
2017: Advances in Experimental Medicine and Biology
https://www.readbyqxmd.com/read/29169417/-overexpression-of-ppenk-reduces-myocardial-ischemia-reperfusion-injury-by-promoting-mitophagy-in-rats
#10
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
#11
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/29160309/structure-of-pink1-in-complex-with-its-substrate-ubiquitin
#12
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/29159229/interactions-of-manganese-with-iron-zinc-and-copper-in-neonatal-c57bl-6j-and-parkin-mice-following-developmental-oral-manganese-exposure
#13
Melanie L Foster, Thomas B Bartnikas, Hailey C Maresca-Fichter, Courtney Mercadante, Miriam Dash, Chelsea Miller, David C Dorman
High dose manganese (Mn) exposure can result in changes in tissue concentrations of other essential metals due to Mn-induced alterations in metal absorption and competition for metal transporters and regulatory proteins. We evaluated responses in mice with a Parkin gene defect (parkin mice) and a wildtype strain (C57BL/6J) following neonatal Mn exposure. Neonatal parkin and C57BL/6J littermates were randomly assigned to 0, 11, or 25 mg Mn/kg-day dose groups with oral exposures occurring from postnatal day (PND) 1 through PND 28...
December 2017: Data in Brief
https://www.readbyqxmd.com/read/29138676/resveratrol-modulation-of-protein-expression-in-parkin-mutant-human-skin-fibroblasts-a-proteomic-approach
#14
Daniele Vergara, Antonio Gaballo, Anna Signorile, Anna Ferretta, Paola Tanzarella, Consiglia Pacelli, Marco Di Paola, Tiziana Cocco, Michele Maffia
In this study, we investigated by two-dimensional gel electrophoresis (2-DE) and mass spectrometry (MS) analysis the effects of resveratrol treatment on skin primary fibroblasts from a healthy subject and from a parkin-mutant early onset Parkinson's disease patient. Parkin, an E3 ubiquitin ligase, is the most frequently mutated gene in hereditary Parkinson's disease. Functional alteration of parkin leads to impairment of the ubiquitin-proteasome system, resulting in the accumulation of misfolded or aggregated proteins accountable for the neurodegenerative process...
2017: Oxidative Medicine and Cellular Longevity
https://www.readbyqxmd.com/read/29124790/neuropathology-of-genetic-synucleinopathies-with-parkinsonism-review-of-the-literature
#15
REVIEW
Susanne A Schneider, Roy N Alcalay
Clinical-pathological studies remain the gold-standard for the diagnosis of Parkinson's disease (PD). However, mounting data from genetic PD autopsies challenge the diagnosis of PD based on Lewy body pathology. Most of the confirmed genetic risks for PD show heterogenous neuropathology, even within kindreds, which may or may not include Lewy body pathology. We review the literature of genetic PD autopsies from cases with molecularly confirmed PD or parkinsonism and summarize main findings on SNCA (n = 25), Parkin (n = 20, 17 bi-allelic and 3 heterozygotes), PINK1 (n = 5, 1 bi-allelic and 4 heterozygotes), DJ-1 (n = 1), LRRK2 (n = 55), GBA (n = 10 Gaucher disease patients with parkinsonism), DNAJC13, GCH1, ATP13A2, PLA2G6 (n = 8 patients, 2 with PD), MPAN (n = 2), FBXO7, RAB39B, and ATXN2 (SCA2), as well as on 22q deletion syndrome (n = 3)...
November 2017: Movement Disorders: Official Journal of the Movement Disorder Society
https://www.readbyqxmd.com/read/29111184/neuron-protective-effect-of-subanesthestic-dosage-ketamine-on-mice-of-parkinson-s-disease
#16
Jun-Chao Fan, Jun-Jie Song, Ying Wang, Ying Chen, Dao-Xian Hong
OBJECTIVE: To discuss the neuron-protective effect and possible mechanism of subanesthestic-dosage ketamine on Parkinson's disease mice induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. METHODS: A total of 30 mice were divided equally into three groups, model control group (MC group), ketamine treatment group (KT group), and blank control group (BC group), respectively. The Parkinson's disease mice of MC group and KT groups were established by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (20 mg/kg/d), while mice in KT group were treated by intraperitoneal injection of subanesthestic-dosage ketamine (8 mg/kg)...
October 2017: Asian Pacific Journal of Tropical Medicine
https://www.readbyqxmd.com/read/29054108/increase-in-pro-apoptotic-activity-of-inhibitory-pas-domain-protein-via-phosphorylation-by-mk2
#17
Shuya Kasai, Mary Jane Elizabeth Richardson, Satoru Torii, Ken-Ichi Yasumoto, Hiroki Shima, Kazuhiko Igarashi, Ken Itoh, Kazuhiro Sogawa, Kazutaka Murayama
Inhibitory PAS domain protein (IPAS) is a bifunctional protein that downregulates hypoxic gene expression and exerts pro-apoptotic activity by preventing pro-survival activity of Bcl-xL and its related factors. Pro-apoptotic activity of IPAS is attenuated by the activation of the PINK1-Parkin pathway, and involved in neuronal degeneration in an experimental mouse model of Parkinson's disease. The current study shows that phosphorylation of IPAS at Ser184 by MAPK-activated protein kinase 2 (MK2 or MAPKAPK2) enhances the pro-apoptotic function of IPAS...
October 20, 2017: FEBS Journal
https://www.readbyqxmd.com/read/29040870/parkin-absence-accelerates-microtubule-aging-in-dopaminergic-neurons
#18
Daniele Cartelli, Alida Amadeo, Alessandra Maria Calogero, Francesca Vittoria Marialuisa Casagrande, Carmelita De Gregorio, Mariarosa Gioria, Naoko Kuzumaki, Ilaria Costa, Jenny Sassone, Andrea Ciammola, Nobutaka Hattori, Hideyuki Okano, Stefano Goldwurm, Laurent Roybon, Gianni Pezzoli, Graziella Cappelletti
Loss-of-function caused by mutations in the parkin gene (PARK2) lead to early-onset familial Parkinson's disease. Recently, mechanistic studies proved the ability of parkin in regulating mitochondria homeostasis and microtubule (MT) stability. Looking at these systems during aging of PARK2 knockout mice, we found that loss of parkin induced an accelerated (over)acetylation of MT system both in dopaminergic neuron cell bodies and fibers, localized in the substantia nigra and corpus striatum, respectively. Interestingly, in PARK2 knockout mice, changes of MT stability preceded the alteration of mitochondria transport...
September 20, 2017: Neurobiology of Aging
https://www.readbyqxmd.com/read/29038162/systematic-analysis-of-human-cells-lacking-atg8-proteins-uncovers-roles-for-gabaraps-and-the-ccz1-mon1-regulator-c18orf8-rmc1-in-macro-and-selective-autophagic-flux
#19
Laura Pontano Vaites, Joao A Paulo, Edward L Huttlin, J Wade Harper
Selective and macro autophagy sequester specific organelles/substrates or bulk cytoplasm, respectively, inside autophagosomes as cargo for delivery to lysosomes. The mammalian ATG8 orthologues (MAP1LC3A/B/C and GABARAP/L1/L2) are ubiquitin (UB)-like proteins conjugated to the autophagosome membrane and are thought to facilitate cargo receptor recruitment, vesicle maturation, and lysosomal fusion. To elucidate the molecular functions of the ATG8 proteins, we engineered cells lacking genes for each subfamily as well as all six mammalian ATG8s...
October 16, 2017: Molecular and Cellular Biology
https://www.readbyqxmd.com/read/29020610/neonatal-c57bl-6j-and-parkin-mice-respond-differently-following-developmental-manganese-exposure-result-of-a-high-dose-pilot-study
#20
Melanie L Foster, Thomas B Bartnikas, Hailey C Maresca-Fichter, Courtney Mercadante, Miriam Dash, Chelsea Miller, David C Dorman
It has been suggested that childhood exposure to neurotoxicants may increase the risk of Parkinson's disease (PD) or other neurodegenerative disease in adults. Some recessive forms of PD have been linked to loss-of-function mutations in the Park2 gene that encodes for parkin. The purpose of this pilot study was to evaluate whether responses to neonatal manganese (Mn) exposure differ in mice with a Park2 gene defect (parkin mice) when compared with a wildtype strain (C57BL/6J). Neonatal parkin and C57BL/6J littermates were randomly assigned to 0, 11, or 25mg Mn/kg-day dose groups with oral exposures occurring from postnatal day (PND) 1 through PND 28...
October 8, 2017: Neurotoxicology
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