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https://www.readbyqxmd.com/read/28860335/activation-mechanisms-of-the-e3-ubiquitin-ligase-parkin
#1
REVIEW
Nikhil Panicker, Valina L Dawson, Ted M Dawson
Monogenetic, familial forms of Parkinson's disease (PD) only account for 5-10% of the total number of PD cases, but analysis of the genes involved therein is invaluable to understanding PD-associated neurodegenerative signaling. One such gene, parkin, encodes a 465 amino acid E3 ubiquitin ligase. Of late, there has been considerable interest in the role of parkin signaling in PD and in identifying its putative substrates, as well as the elucidation of the mechanisms through which parkin itself is activated...
August 30, 2017: Biochemical Journal
https://www.readbyqxmd.com/read/28851515/alterations-in-the-e3-ligases-parkin-and-chip-result-in-unique-metabolic-signaling-defects-and-mitochondrial-quality-control-issues
#2
REVIEW
Britney N Lizama, Amy M Palubinsky, BethAnn McLaughlin
E3 ligases are essential scaffold proteins, facilitating the transfer of ubiquitin from E2 enzymes to lysine residues of client proteins via isopeptide bonds. The specificity of substrate binding and the expression and localization of E3 ligases can, however, endow these proteins with unique features with variable effects on mitochondrial, metabolic and CNS function. By comparing and contrasting two E3 ligases, Parkin and C-terminus of HSC70-Interacting protein (CHIP) we seek to highlight the biophysical properties that may promote mitochondrial dysfunction, acute stress signaling and critical developmental periods to cease in response to mutations in these genes...
August 26, 2017: Neurochemistry International
https://www.readbyqxmd.com/read/28816645/a-systems-model-of-parkinson-s-disease-using-biochemical-systems-theory
#3
Hemalatha Sasidharakurup, Nidheesh Melethadathil, Bipin Nair, Shyam Diwakar
Parkinson's disease (PD), a neurodegenerative disorder, affects millions of people and has gained attention because of its clinical roles affecting behaviors related to motor and nonmotor symptoms. Although studies on PD from various aspects are becoming popular, few rely on predictive systems modeling approaches. Using Biochemical Systems Theory (BST), this article attempts to model and characterize dopaminergic cell death and understand pathophysiology of progression of PD. PD pathways were modeled using stochastic differential equations incorporating law of mass action, and initial concentrations for the modeled proteins were obtained from literature...
August 2017: Omics: a Journal of Integrative Biology
https://www.readbyqxmd.com/read/28803490/parkin-pink1-and-dj1-as-possible-modulators-of-mtor-pathway-in-ganglioglioma
#4
Katarzyna Drapalo, Jaroslaw Jozwiak
Ganglioglioma (GG) is a non-malignant tumor classified as G1 by the WHO. Although we currently know that the neoplasm may result from the hyperactivity of protein kinase B (PKB or Akt) or extracellular-regulated kinase (Erk), which upregulates mammalian target of rapamycin kinase (mTOR) and leads to translation of proteins responsible for cell cycle regulation, there are still many questions to be answered. In the current paper we try to analyze the link between GG formation and activity of three proteins known to play a role in neuroprotection...
August 14, 2017: International Journal of Neuroscience
https://www.readbyqxmd.com/read/28802919/nonmotor-signs-in-genetic-forms-of-parkinson-s-disease
#5
Meike Kasten, Connie Marras, Christine Klein
Although only a minority (i.e., ~5%) of Parkinson's disease (PD) cases is due to well-defined genetic causes, important clues about the common, "idiopathic" PD (iPD) can be garnered from monogenic model diseases. Nonmotor signs (NMS) are also present in monogenic PD and reviewed in this chapter for the confirmed PD genes SNCA, LRRK2, VPS35, Parkin, PINK1, DJ-1, and the risk factor gene GBA. Within the context of the MDSGene database (www.mdsgene.org), we performed a systematic literature search and extracted information on cognitive decline, depression, psychotic signs and symptoms, autonomic signs and symptoms, anxiety, sleep disorder, and olfactory impairment...
2017: International Review of Neurobiology
https://www.readbyqxmd.com/read/28799502/mitochondrial-dynamics-and-proteins-related-to-neurodegenerative-diseases
#6
Athanasios Alexiou, Bilal Nizami, Faez Iqbal Khan, Georgia Soursou, Charalampos Vairaktarakis, Stylianos Chatzichronis, Vasilis Tsiamis, Vasileios Manztavinos, Nagendra Sastry Yarla, Ghulam Md Ashraf
Disruptions in the regulation of mitochondrial dynamics and the occurrence of proteins misfolding lead to neuronal death, resulting in Age-related Dementia and Neurodegenerative diseases as well as Frailty. Functional, neurophysiologic and biochemical alterations within the mitochondrial populations can reveal deficits in brain energy metabolism resulting in Mild Cognitive Impairment, abnormal neural development, autonomic dysfunction and other mitochondrial disorders. Additionally, in cases of Alzheimer's disease or Parkinson's disease, a significant number of proteins seems to form unordered and problematic structures, leading through unknown mechanisms to pathological conditions...
August 10, 2017: Current Protein & Peptide Science
https://www.readbyqxmd.com/read/28789629/early-onset-parkinson-s-disease-in-a-family-of-moroccan-origin-caused-by-a-p-a217d-mutation-in-pink1-a-case-report
#7
Brendan P Norman, Steven J Lubbe, Manuela Tan, Naomi Warren, Huw R Morris
BACKGROUND: Bi-allelic mutations in the genes Parkin (PARK2), PINK1 (PARK6) and DJ-1 (PARK7) are established causes of autosomal recessive early-onset Parkinson's Disease (EOPD). PINK1 mutations are the second commonest cause of EOPD. Specific mutations may be relatively common in certain populations because of a founder effect. Homozygous p.A217D PINK1 mutations were previously shown to cause EOPD in a large Sudanese kindred. CASE PRESENTATION: Here we report the segregation of homozygous PINK1 p...
August 8, 2017: BMC Neurology
https://www.readbyqxmd.com/read/28782874/in-vivo-imaging-reveals-mitophagy-independence-in-the-maintenance-of-axonal-mitochondria-during-normal-aging
#8
Xu Cao, Haiqiong Wang, Zhao Wang, Qingyao Wang, Shuang Zhang, Yuanping Deng, Yanshan Fang
Mitophagy is thought to be a critical mitochondrial quality control mechanism in neurons and has been extensively studied in neurological disorders such as Parkinson's disease. However, little is known about how mitochondria are maintained in the lengthy neuronal axons in the context of physiological aging. Here, we utilized the unique Drosophila wing nerve model and in vivo imaging to rigorously profile changes in axonal mitochondria during aging. We revealed that mitochondria became fragmented and accumulated in aged axons...
October 2017: Aging Cell
https://www.readbyqxmd.com/read/28768533/progression-of-pathology-in-pink1-deficient-mouse-brain-from-splicing-via-ubiquitination-er-stress-and-mitophagy-changes-to-neuroinflammation
#9
Sylvia Torres-Odio, Jana Key, Hans-Hermann Hoepken, Júlia Canet-Pons, Lucie Valek, Bastian Roller, Michael Walter, Blas Morales-Gordo, David Meierhofer, Patrick N Harter, Michel Mittelbronn, Irmgard Tegeder, Suzana Gispert, Georg Auburger
BACKGROUND: PINK1 deficiency causes the autosomal recessive PARK6 variant of Parkinson's disease. PINK1 activates ubiquitin by phosphorylation and cooperates with the downstream ubiquitin ligase PARKIN, to exert quality control and control autophagic degradation of mitochondria and of misfolded proteins in all cell types. METHODS: Global transcriptome profiling of mouse brain and neuron cultures were assessed in protein-protein interaction diagrams and by pathway enrichment algorithms...
August 2, 2017: Journal of Neuroinflammation
https://www.readbyqxmd.com/read/28765939/molecular-dynamics-simulations-of-human-e3-ubiquitin-ligase-parkin
#10
Shi Qiu, Shun Zhu, Shan Xu, Yanyan Han, Wen Liu, Ji Zuo
Human E3 ubiquitin protein ligase parkin (Parkin) mediates mitophagy to maintain mitochondrial homeostasis. Parkin mutations are common genetic causes of early onset familial Parkinson's disease. The molecular mechanism of Parkin activation has been widely studied with emerging evidence suggesting an essential role of the phosphorylated (phospho)‑ubiquitin interaction. However, the underlying mecha-nism of the phospho‑ubiquitin interaction remains elusive. In the present study, replica exchange molecular dynamics simulations were performed to examine the conformational dynamics of Parkin in monomer and phospho‑ubiquitin‑bound states...
October 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/28733540/am1241-alleviates-mptp-induced-parkinson-s-disease-and-promotes-the-regeneration-of-da-neurons-in-pd-mice
#11
Jun Shi, Qiong Cai, Jingxing Zhang, Xiaolie He, Yigang Liu, Rongrong Zhu, Lingjing Jin
The main pathological feature of Parkinson's disease (PD) is the loss of dopaminergic neurons in the substantia nigra. In this study, we investigated the role of cannabinoid receptor 2 (CB2R) agonist AM1241 on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity in a mouse model of PD. Upon treatment with AM1241, the decreased CB2R level in the PD mouse brain was reversed and the behavior score markedly elevated, accompanied with a dose-dependent increase of dopamine and serotonin. In addition, western blot assay and immunostaining results suggested that AM1241 significantly activated PI3K/Akt/MEK phosphorylation and increased the expression of Parkin and PINK1, both in the substantia nigra and hippocampus...
June 29, 2017: Oncotarget
https://www.readbyqxmd.com/read/28724963/midnolin-is-a-novel-regulator-of-parkin-expression-and-is-associated-with-parkinson-s-disease
#12
Yutaro Obara, Toru Imai, Hidenori Sato, Yuji Takeda, Takeo Kato, Kuniaki Ishii
Midnolin (MIDN) was first discovered in embryonic stem cells, but its physiological and pathological roles are, to date, poorly understood. In the present study, we therefore examined the role of MIDN in detail. We found that in PC12 cells, a model of neuronal cells, MIDN localized primarily to the nucleus and intracellular membranes. Nerve growth factor promoted MIDN gene expression, which was attenuated by specific inhibitors of extracellular signal-regulated kinases 1/2 and 5. MIDN-deficient PC12 cells created using CRISPR/Cas9 technology displayed significantly impaired neurite outgrowth...
July 19, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28716221/parkin-mutation-may-be-associated-with-serious-akinesia-in-a-patient-with-parkinson-s-disease
#13
Yuto Uchihara, Hiroshi Kataoka, Hiroyo Yoshino, Ryogo Syobatake, Nobutaka Hattori, Satoshi Ueno
Acute akinesia (AA) is an unusual motor complication in Parkinson's disease (PD). Reported risk factors for AA include infection, trauma, surgical intervention, and the withdrawal of antiparkinsonian medication. Recently, patients with genetic PD were reported to have a three-fold risk of AA than patients with non-genetic PD. We describe a patient with PD associated with a Parkin mutation in whom serious akinesia developed. A 42-year-old man with exon 2 heterozygous deletion and exon 4 heterozygous deletion in the PARK2 gene showed five unexpected AA for several 12h...
August 15, 2017: Journal of the Neurological Sciences
https://www.readbyqxmd.com/read/28711655/ubiquitination-at-the-mitochondria-in-neuronal-health-and-disease
#14
REVIEW
Christian Covill-Cooke, Jack Howden, Nicol Birsa, Josef Kittler
The preservation of mitochondrial function is of particular importance in neurons given the high energy requirements of action potential propagation and synaptic transmission. Indeed, disruptions in mitochondrial dynamics and quality control are linked to cellular pathology in neurodegenerative diseases, such as Alzheimer's and Parkinson's disease. Here, we will discuss the role of ubiquitination by the E3 ligases: Parkin, MARCH5 and Mul1, and how they regulate mitochondrial homeostasis. Furthermore, given the role of Parkin and Mul1 in the formation of mitochondria-derived vesicles we give an overview of this area of mitochondrial homeostasis...
July 12, 2017: Neurochemistry International
https://www.readbyqxmd.com/read/28695462/transgenic-mice-overexpressing-the-divalent-metal-transporter-1-exhibit-iron-accumulation-and-enhanced-parkin-expression-in-the-brain
#15
Cheng-Wu Zhang, Yee Kit Tai, Bing-Han Chai, Katherine C M Chew, Eng-Tat Ang, Fai Tsang, Bryce W Q Tan, Eugenia T E Hong, Abu Bakar Ali Asad, Kai-Hsiang Chuang, Kah-Leong Lim, Tuck Wah Soong
Exposure to divalent metals such as iron and manganese is thought to increase the risk for Parkinson's disease (PD). Under normal circumstances, cellular iron and manganese uptake is regulated by the divalent metal transporter 1 (DMT1). Accordingly, alterations in DMT1 levels may underlie the abnormal accumulation of metal ions and thereby disease pathogenesis. Here, we have generated transgenic mice overexpressing DMT1 under the direction of a mouse prion promoter and demonstrated its robust expression in several regions of the brain...
July 10, 2017: Neuromolecular Medicine
https://www.readbyqxmd.com/read/28689991/ubiquitin-phosphorylated-at-ser57-hyper-activates-parkin
#16
Susanna George, Sabrina M Wang, Yumin Bi, Margot Treidlinger, Kathryn R Barber, Gary S Shaw, Patrick O'Donoghue
Malfunction of the ubiquitin (Ub) E3 ligase, parkin, leads to defects in mitophagy and protein quality control linked to Parkinson's disease. Parkin activity is stimulated by phosphorylation of Ub at Ser65 (pUb(S65)). Since the upstream kinase is only known for Ser65 (PINK1), the biochemical function of other phosphorylation sites on Ub remain largely unknown. We used fluorescently labelled and site-specifically phosphorylated Ub substrates to quantitatively relate the position and stoichiometry of Ub phosphorylation to parkin activation...
July 6, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28688199/differential-expression-of-park2-splice-isoforms-in-an-in-vitro-model-of-dopaminergic-like-neurons-exposed-to-toxic-insults-mimicking-parkinson-s-disease
#17
Valentina La Cognata, Grazia Maugeri, Agata Grazia D'Amico, Salvatore Saccone, Concetta Federico, Sebastiano Cavallaro, Velia D'Agata
Mutations in PARK2 (or parkin) are responsible for 50% of cases of autosomal-recessive juvenile-onset Parkinson's disease (PD). To date, 21 alternative splice variants of the human gene have been cloned. Yet most studies have focused on the full-length protein, whereas the spectrum of the parkin isoforms expressed in PD has never been investigated. In this study, the role of parkin proteins in PD neurodegeneration was explored for the first time by analyzing their expression profile in an in vitro model of PD...
July 8, 2017: Journal of Cellular Biochemistry
https://www.readbyqxmd.com/read/28661099/self-administration-of-methamphetamine-alters-gut-biomarkers-of-toxicity
#18
Amanda Flack, Amanda L Persons, Sharanya M Kousik, T Celeste Napier, Anna Moszczynska
Methamphetamine (METH) is a highly abused psychostimulant that is associated with an increased risk for developing Parkinson's disease (PD). This enhanced vulnerability likely relates to the toxic effects of METH that overlap with PD pathology, for example, aberrant functioning of α-synuclein and parkin. In PD, peripheral factors are thought to contribute to central nervous system (CNS) degeneration. For example, α-synuclein levels in the enteric nervous system (ENS) are elevated, and this precedes the onset of motor symptoms...
August 2017: European Journal of Neuroscience
https://www.readbyqxmd.com/read/28656059/parkin-knockout-inhibits-neuronal-development-via-regulation-of-proteasomal-degradation-of-p21
#19
Mi Hee Park, Hwa-Jeong Lee, Hye Lim Lee, Dong Ju Son, Jung Hoon Ju, Byung Kook Hyun, Sung Hee Jung, Ju-Kyoung Song, Dong Hun Lee, Chul Ju Hwang, Sang Bae Han, Sanghyeon Kim, Jin Tae Hong
PARK2 encodes for the E3 ubiquitin ligase parkin and is implicated in the development of Parkinson's disease (PD). Although the neuroprotective role of parkin is well known, the mechanism of PARK2's function in neural stem differentiation has not yet been thoroughly studied. Co-expressions network analysis showed that synaptosomal-associated protein 25 (SNAP-25) and brain-derived neurotrophic factor (BDNF) were positively correlated with parkin, but negatively correlated with p21 in human patient brain. We investigated a link between the ubiquitin E3 ligase parkin and proteasomal degradation of p21 for the control of neural stem cell differentiation...
2017: Theranostics
https://www.readbyqxmd.com/read/28629580/folding-underlies-bidirectional-role-of-gpr37-pael-r-in-parkinson-disease
#20
REVIEW
Lina Leinartaité, Per Svenningsson
Since conformational flexibility, which is required for the function of a protein, comes at the expense of structural stability, many proteins, including G-protein-coupled receptors (GPCRs), are under constant risk of misfolding and aggregation. In this regard GPR37 (also named PAEL-R and ETBR-LP-1) takes a prominent role, particularly in relation to Parkinson disease (PD). GPR37 is a substrate for parkin and accumulates abnormally in autosomal recessive juvenile parkinsonism, contributing to endoplasmic reticulum stress and death of dopaminergic neurons...
June 16, 2017: Trends in Pharmacological Sciences
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