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https://www.readbyqxmd.com/read/28078567/the-c-abl-inhibitor-in-parkinson-disease
#1
REVIEW
Zhi-Hua Zhou, Yun-Fan Wu, Xue-Min Wang, Yong-Zhu Han
Parkinson's disease (PD) is an insidious onset neurodegenerative disease affecting approximately 1% of the population over the age of 65. So far available therapies for PD have only aimed at improving or alleviating symptoms, but not at slowing, preventing, and reversing the course of PD. Recently, some studies have indicated that the levels and activation of Abelson non-receptor tyrosine kinase (c-Abl, Abl1) were up-regulated in the brain tissue of patients with PD and demonstrated that c-Abl inhibitors could improve motor behavior, prevent the loss of dopamine neurons, inhibit phosphorylation of Cdk5, regulate α-synuclein phosphorylation and clearance, inhibit the tyrosine phosphorylation of parkin and decrease parkin substrate, for example, PARIS (zinc finger protein 746), AIMP2 (aminoacyl-tRNA synthetase-interacting multifunctional protein type2), FBP1 (fuse-binding protein 1), and synphilin-1...
January 11, 2017: Neurological Sciences
https://www.readbyqxmd.com/read/28053050/parkin-functionally-interacts-with-pgc-1%C3%AE-to-preserve-mitochondria-and-protect-dopaminergic-neurons
#2
Lu Zheng, Nathalie Bernard-Marissal, Norman Moullan, Davide D'Amico, Johan Auwerx, Darren J Moore, Graham Knott, Patrick Aebischer, Bernard L Schneider
To understand the cause of Parkinson's disease (PD), it is important to determine the functional interactions between factors linked to the disease. Parkin is associated to autosomal recessive early-onset PD, and controls the transcription of PGC-1α, a master regulator of mitochondrial biogenesis. These two factors functionally interact to regulate the turnover and quality of mitochondria, by increasing both mitophagic activity and mitochondria biogenesis. In cortical neurons, co-expressing PGC-1α and Parkin increases the number of mitochondria, enhances maximal respiration, and accelerates the recovery of the mitochondrial membrane potential following mitochondrial uncoupling...
January 4, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28042771/oxidative-stress-pro-inflammatory-cytokines-and-antioxidants-regulate-expression-levels-of-micrornas-in-parkinson-s-disease
#3
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/28042097/parkin-deficiency-accelerates-consequences-of-mitochondrial-dna-deletions-and-parkinsonism
#4
Lanying Song, Marissa McMackin, Andy Nguyen, Gino Cortopassi
Parkinson's disease (PD) is a neurodegenerative condition caused by age-related death of dopaminergic (DA) neurons in the substantia nigra (SN). Mitochondrial DNA (mtDNA) deletions rise exponentially with age in humans and reach their highest levels approaching 60% in dopaminergic neurons of the substantia nigra and overlap with dying neurons. Parkin deletion causes Parkinsonism in humans, presumably through a decrease in mitochondrial quality control, but Parkin knockout mice do not have DA neurodegeneration...
December 29, 2016: Neurobiology of Disease
https://www.readbyqxmd.com/read/28017782/parkin-and-pink1-functions-in-oxidative-stress-and-neurodegeneration
#5
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
#6
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
#7
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/27911343/pink1-parkin-and-mitochondrial-quality-control-what-can-we-learn-about-parkinson-s-disease-pathobiology
#8
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
#9
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
#10
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
#11
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
#12
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
#13
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
#14
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
#15
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
#16
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
#17
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
SEE GANDHI AND PLUN-FAVREAU DOI101093/AWW320 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: 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...
January 2017: 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
#18
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
#19
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
#20
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
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