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parkin and parkinson disease

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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/27833551/c-abl-inhibitors-enable-insights-into-the-pathophysiology-and-neuroprotection-in-parkinson-s-disease
#6
REVIEW
Dan Lindholm, Dan D Pham, Annunziata Cascone, Ove Eriksson, Krister Wennerberg, Mart Saarma
Parkinson's disease (PD) is a progressive neurodegenerative disorder causing movement disabilities and several non-motor symptoms in afflicted patients. Recent studies in animal models of PD and analyses of brain specimen from PD patients revealed an increase in the level and activity of the non-receptor tyrosine kinase Abelson (c-Abl) in dopaminergic neurons with phosphorylation of protein substrates, such as α-synuclein and the E3 ubiquitin ligase, Parkin. Most significantly inhibition of c-Abl kinase activity by small molecular compounds used in the clinic to treat human leukemia have shown promising neuroprotective effects in cell and animal models of PD...
2016: Frontiers in Aging Neuroscience
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
#7
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
#8
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
#9
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/27807026/heterozygous-pink1-p-g411s-increases-risk-of-parkinson-s-disease-via-a-dominant-negative-mechanism
#10
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
#11
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/27761515/swath-ms-proteome-profiling-data-comparison-of-dj-1-parkin-and-pink1-knockout-rat-striatal-mitochondria
#12
Kelly L Stauch, Lance M Villeneuve, Phillip R Purnell, Sanjit Pandey, Chittibabu Guda, Howard S Fox
This article reports changes in the striatal non-synaptic mitochondrial proteome of DJ-1, Parkin, and PINK1 knockout (KO) rats at 3 months of age. DJ-1, Parkin, and PINK1 mutations cause autosomal-recessive parkinsonism. It is thought that loss of function of these proteins contributes to the onset and pathogenesis of Parkinson׳s disease (PD). As DJ-1, Parkin, and PINK1 have functions in the regulation of mitochondria, the dataset generated here highlights protein expression changes, which can be helpful for understanding pathological mitochondrial alterations...
December 2016: Data in Brief
https://www.readbyqxmd.com/read/27722926/mpp-lesioned-mice-an-experimental-model-of-motor-emotional-memory-learning-and-striatal-neurochemical-dysfunctions
#13
Mauricio P Cunha, Francis L Pazini, Vicente Lieberknecht, Josiane Budni, Ágatha Oliveira, Júlia M Rosa, Gianni Mancini, Leidiane Mazzardo, André R Colla, Marina C Leite, Adair R S Santos, Daniel F Martins, Andreza F de Bem, Carlos Alberto S Gonçalves, Marcelo Farina, Ana Lúcia S Rodrigues
The neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induces motor and nonmotor dysfunctions resembling Parkinson's disease (PD); however, studies investigating the effects of 1-methyl-4-phenylpyridinium (MPP(+)), an active oxidative product of MPTP, are scarce. This study investigated the behavioral and striatal neurochemical changes (related to oxidative damage, glial markers, and neurotrophic factors) 24 h after intracerebroventricular administration of MPP(+) (1.8-18 μg/mouse) in C57BL6 mice...
October 8, 2016: Molecular Neurobiology
https://www.readbyqxmd.com/read/27720857/low-protein-to-carbohydrate-ratio-diet-delays-onset-of-parkinsonism-like-phenotype-in-drosophila-melanogaster-parkin-null-mutants
#14
Rijan Bajracharya, J William O Ballard
Dietary management plays a key role in the treatment of many diseases. However, no prospective studies have critically investigated the potential for dietary modification to delay the onset, or slow the progression, of Parkinson's Disease (PD). To study whether manipulating the Protein to Carbohydrate (P:C) ratio in the diet could affect the progression of PD, we compared Drosophila melanogaster parkin null mutants and their experimental controls fed with diets differing in their P:C ratio. We considered lifespan and feeding behaviors as well as motor and cellular functions on the 1:2 and 1:16 P:C diets...
October 6, 2016: Mechanisms of Ageing and Development
https://www.readbyqxmd.com/read/27720484/a-lrrk2-dependent-endophilina-phosphoswitch-is-critical-for-macroautophagy-at-presynaptic-terminals
#15
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
#16
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/27709117/genetic-and-clinical-predictors-of-deep-brain-stimulation-in-young-onset-parkinson-s-disease
#17
Gian D Pal, Deborah Hall, Bichun Ouyang, Jessica Phelps, Roy Alcalay, Michael W Pauciulo, William C Nichols, Lorraine Clark, Helen Mejia-Santana, Lucia Blasucci, Christopher G Goetz, Cynthia Comella, Amy Colcher, Ziv Gan-Or, Guy A Rouleau, Karen Marder
OBJECTIVE: In a cohort of patients with young-onset Parkinson's disease (PD), the authors assessed (1) the prevalence of genetic mutations in those who enrolled in deep brain stimulation (DBS) programs compared with those who did not enroll DBS programs and (2) specific genetic and clinical predictors of DBS enrollment. METHODS: Subjects were participants from 3 sites (Columbia University, Rush University, and the University of Pennsylvania) in the Consortium on Risk for Early Onset Parkinson's Disease (CORE-PD) who had an age at onset < 51 years...
September 2016: Movement Disorders Clinical Practice
https://www.readbyqxmd.com/read/27703082/fluorescent-parkin-cell-based-assay-development-for-the-screening-of-drugs-against-parkinson-disease
#18
Patricia Villacé, Rosa M Mella, Meritxell Roura-Ferrer, María Valcárcel, Clarisa Salado, Amaia Castilla, Danel Kortazar
Parkinson disease (PD) is a prevalent neurodegenerative disease characterized by selective degeneration of dopaminergic neurons in the substantia nigra, causing tremor and motor impairment. Parkin protein, whose mutants are the cause of Parkinson disease type 2 (PARK2), has been mechanistically linked to the regulation of apoptosis and the turnover of damaged mitochondria. Several studies have implicated aberrant mitochondria as a key contributor to the development of PD. In the attempt to discover new drugs, high-content cell-based assays are becoming more important to mimic the nature of biological processes and their diversifications in diseases and will be essential for lead identification and the optimization of therapeutic candidates...
October 4, 2016: Journal of Biomolecular Screening
https://www.readbyqxmd.com/read/27693468/parkin-regulates-lipopolysaccharide-induced-proinflammatory-responses-in-acute-lung-injury
#19
Eleftheria Letsiou, Saad Sammani, Huashan Wang, Patrick Belvitch, Steven M Dudek
The acute respiratory distress syndrome (ARDS) is a serious condition resulting from direct or indirect lung injury that is associated with high mortality and morbidity. A key biological event in the pathogenesis of the acute lung injury (ALI) that causes acute respiratory distress syndrome is activation of the lung endothelium cells (ECs), which is triggered by a variety of inflammatory insults leading to barrier disruption and excessive accumulation of neutrophils. Recently, we demonstrated that imatinib protects against lipopolysaccharide (LPS)-induced EC activation by inhibiting c-Abl kinase...
September 13, 2016: Translational Research: the Journal of Laboratory and Clinical Medicine
https://www.readbyqxmd.com/read/27641647/parkin-and-pink1-patient-ipsc-derived-midbrain-dopamine-neurons-exhibit-mitochondrial-dysfunction-and-%C3%AE-synuclein-accumulation
#20
Sun Young Chung, Sarah Kishinevsky, Joseph R Mazzulli, John Graziotto, Ana Mrejeru, Eugene V Mosharov, Lesly Puspita, Parvin Valiulahi, David Sulzer, Teresa A Milner, Tony Taldone, Dimitri Krainc, Lorenz Studer, Jae-Won Shim
Parkinson's disease (PD) is characterized by the selective loss of dopamine neurons in the substantia nigra; however, the mechanism of neurodegeneration in PD remains unclear. A subset of familial PD is linked to mutations in PARK2 and PINK1, which lead to dysfunctional mitochondria-related proteins Parkin and PINK1, suggesting that pathways implicated in these monogenic forms could play a more general role in PD. We demonstrate that the identification of disease-related phenotypes in PD-patient-specific induced pluripotent stem cell (iPSC)-derived midbrain dopamine (mDA) neurons depends on the type of differentiation protocol utilized...
October 11, 2016: Stem Cell Reports
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