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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/27903732/parkin-deficiency-reduces-hippocampal-glutamatergic-neurotransmission-by-impairing-ampa-receptor-endocytosis
#4
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
#5
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
#6
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
#7
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/27834372/the-pangenome-of-an-agronomically-important-crop-plant-brassica-oleracea
#8
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
#9
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
#10
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
#11
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/27808473/extensive-homoeologous-genome-exchanges-in-allopolyploid-crops-revealed-by-mrnaseq-based-visualization
#12
Z He, L Wang, A L Harper, L Havlickova, A K Pradhan, I A P Parkin, I Bancroft
Polyploidy, the possession of multiple sets of chromosomes, has been a predominant factor in the evolution and success of the angiosperms. Although artificially formed allopolyploids show a high rate of genome rearrangement, the genomes of cultivars and germplasm used for crop breeding were assumed stable and genome structural variation under the artificial selection process of commercial breeding has remained little studied. Here we show, using a repurposed visualization method based on transcriptome sequence data, that genome structural rearrangement occurs frequently in varieties of three polyploid crops (oilseed rape, mustard rape and bread wheat), meaning that the extent of genome structural variation present in commercial crops is much higher than expected...
November 3, 2016: Plant Biotechnology Journal
https://www.readbyqxmd.com/read/27807026/heterozygous-pink1-p-g411s-increases-risk-of-parkinson-s-disease-via-a-dominant-negative-mechanism
#13
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/27798970/second-mutation-in-park2-is-absent-in-patients-with-sporadic-parkinson-s-disease-and-heterozygous-exonic-deletions-duplications-in-parkin-gene
#14
Marina V Shulskaya, Maria I Shadrina, Ekaterina Yu Fedotova, Nataliya Yu Abramycheva, Svetlana A Limborska, Sergey N Illarioshkin, Petr A Slominsky
AIM OF THE STUDY: Mutations in PARK2 are one of the causes of Parkinson's disease (PD). Deletions and duplications/triplications of one exon or exon groups account for a large proportion of mutations in the gene. At the present time, it is still not fully clear whether heterozygous mutations cause the development of PD. Our study aimed at conducting screening for mutations in PARK2 in patients with a sporadic form of PD to clarify the role of PARK2 in the development of PD. MATERIALS AND METHODS: The cohort of 327 patients with PD was screened by quantitative real-time polimerase chain reaction (PCR) with subsequent Sanger sequencing...
November 16, 2016: International Journal of Neuroscience
https://www.readbyqxmd.com/read/27794540/pink1-and-parkin-are-genetic-modifiers-for-fus-induced-neurodegeneration
#15
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
https://www.readbyqxmd.com/read/27770595/microtubule-binding-protein-pacrg-plays-a-role-in-regulating-specific-ciliary-dyneins-during-microtubule-sliding
#16
Katsutoshi Mizuno, Erin E Dymek, Elizabeth F Smith
The complex waveforms characteristic of motile eukaryotic cilia and flagella are produced by the temporally and spatially regulated action of multiple dynein subforms generating sliding between subsets of axonemal microtubules. Multiple protein complexes have been identified that are associated with the doublet microtubules and that mediate regulatory signals between key axonemal structures, such as the radial spokes and central apparatus, and the dynein arm motors; these complexes include the N-DRC, MIA and CSC complexes...
October 22, 2016: Cytoskeleton
https://www.readbyqxmd.com/read/27720484/a-lrrk2-dependent-endophilina-phosphoswitch-is-critical-for-macroautophagy-at-presynaptic-terminals
#17
Sandra-Fausia Soukup, Sabine Kuenen, Roeland Vanhauwaert, Julia Manetsberger, Sergio Hernández-Díaz, Jef Swerts, Nils Schoovaerts, Sven Vilain, Natalia V Gounko, Katlijn Vints, Ann Geens, Bart De Strooper, Patrik Verstreken
Synapses are often far from the soma and independently cope with proteopathic stress induced by intense neuronal activity. However, how presynaptic compartments turn over proteins is poorly understood. We show that the synapse-enriched protein EndophilinA, thus far studied for its role in endocytosis, induces macroautophagy at presynaptic terminals. We find that EndophilinA executes this unexpected function at least partly independent of its role in synaptic vesicle endocytosis. EndophilinA-induced macroautophagy is activated when the kinase LRRK2 phosphorylates the EndophilinA-BAR domain and is blocked in animals where EndophilinA cannot be phosphorylated...
November 23, 2016: Neuron
https://www.readbyqxmd.com/read/27713507/versatile-members-of-the-dnaj-family-show-hsp70-dependent-anti-aggregation-activity-on-ring1-mutant-parkin-c289g
#18
Vaishali Kakkar, E F Elsiena Kuiper, Abhinav Pandey, Ineke Braakman, Harm H Kampinga
Parkinson's disease is one of the most common neurodegenerative disorders and several mutations in different genes have been identified to contribute to the disease. A loss of function parkin RING1 domain mutant (C289G) is associated with autosomal-recessive juvenile-onset Parkinsonism (AR-JP) and displays altered solubility and sequesters into aggregates. Single overexpression of almost each individual member of the Hsp40 (DNAJ) family of chaperones efficiently reduces parkin C289G aggregation and requires interaction with and activity of endogenously expressed Hsp70 s...
October 7, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27638713/gene-therapy-targeting-mitochondrial-pathway-in-parkinson-s-disease
#19
Chi-Jing Choong, Hideki Mochizuki
Parkinson's disease (PD) presents a relative selective localization of pathology to substantia nigra and well-defined motor symptoms caused by dopaminergic degeneration that makes it an ideal target for gene therapy. Parallel progress in viral vector systems enables the delivery of therapeutic genes directly into brain with reasonable safety along with sustained transgene expression. To date, gene therapy for PD that has reached clinical trial evaluation is mainly based on symptomatic approach that involves enzyme replacement strategy and restorative approach that depends on the addition of neurotrophic factors...
September 16, 2016: Journal of Neural Transmission
https://www.readbyqxmd.com/read/27619486/a-novel-tyrosine-hydroxylase-variant-in-a-group-of-chinese-patients-with-dopa-responsive-dystonia
#20
Ya-Ping Yan, Bo Zhang, Yan-Fang Mao, Zhang-Yu Guo, Jun Tian, Guo-Hua Zhao, Jia-Li Pu, Wei Luo, Zhi-Yuan Ouyang, Bao-Rong Zhang
Dopa-responsive dystonia (DRD) comprises a heterogeneous group of movement disorders. A limited number of studies of Chinese patients with DRD have been reported. In the present study, we investigated the clinical and genetic features of 12 Chinese DRD families. Point mutation analysis of the GTP-cyclohydrolase I (GCH1), tyrosine hydroxylase (TH) and sepiapterin reductase (SPR) genes was conducted by direct sequencing. In addition, multiplex ligation-dependent probe amplification targeting GCH1 and TH was performed in "mutation-free" patients...
October 5, 2016: International Journal of Neuroscience
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