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parkin and parkinson disease

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https://www.readbyqxmd.com/read/28629580/folding-underlies-bidirectional-role-of-gpr37-pael-r-in-parkinson-disease
#1
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
https://www.readbyqxmd.com/read/28621812/tcdd-induces-ubch7-expression-and-synphilin-1-protein-degradation-in-the-mouse-ventral-midbrain
#2
Emmanuel González-Barbosa, Alejandro Mejía-García, Elizabeth Bautista, Frank J Gonzalez, José Segovia, Guillermo Elizondo
UbcH7 is an ubiquitin-conjugating enzyme that interacts with parkin, an E3 ligase. The UbcH7-parkin complex promotes the ubiquitination and degradation of several proteins via the 26S proteasome. Cellular accumulation of the UbcH7-parkin targets alpha-synuclein, and synphilin-1 has been associated with Parkinson disease. In mouse liver, 2,3,7,8-tetrachlorodibenzo-p-dioxin, an aryl hydrocarbon receptor ligand, induces UbcH7 expression. Therefore, the aim of the present study was to determine whether 2,3,7,8-tetrachlorodibenzo-p-dioxin induces Ubch7 mRNA and UbcH7 protein expression in the mouse brain, to characterize the molecular mechanism, and the effect on synphilin-1 half-life...
June 16, 2017: Journal of Biochemical and Molecular Toxicology
https://www.readbyqxmd.com/read/28620835/twenty-years-since-the-discovery-of-the-parkin-gene
#3
REVIEW
Nobutaka Hattori, Yoshikuni Mizuno
Nearly 20 years have passed since we identified the causative gene for a familial Parkinson's disease, parkin (now known as PARK2), in 1998. PARK2 is the most common gene responsible for young-onset Parkinson's disease. It codes for the protein Parkin RBR E3 ubiquitin-protein ligase (PARK2), which directly links to the ubiquitin-proteasome as a ubiquitin ligase. PARK2 is involved in mitophagy, which is a type of autophagy, in collaboration with PTEN-induced putative kinase 1 (PINK1). The PINK1 gene (previously known as PARK6) is also a causative gene for young-onset Parkinson's disease...
June 15, 2017: Journal of Neural Transmission
https://www.readbyqxmd.com/read/28598236/destructive-cellular-paths-underlying-familial-and-sporadic-parkinson-disease-converge-on-mitophagy
#4
Xinnan Wang
The knowledge gap separating the molecular and cellular underpinnings of Parkinson disease (PD) and its pathology hinders treatment innovation. Adding to this difficulty is the lack of a reliable biomarker for PD. Our previous studies identify a link of 2 PD proteins, PINK1 and PRKN/Parkin to a mitochondrial motor/adaptor RHOT1/Miro-1, which mediates mitochondrial motility and mitophagy. Here we review our recent paper showing that a third PD protein, LRRK2, also targets RHOT1 and regulates mitophagy, and pathogenic LRRK2 disrupts this function...
June 9, 2017: Autophagy
https://www.readbyqxmd.com/read/28584093/treatment-with-diphenyl-pyrazole-compound-anle138b-c-reveals-that-%C3%AE-synuclein-protects-melanoma-cells-from-autophagic-cell-death
#5
Elisa Turriani, Diana F Lázaro, Sergey Ryazanov, Andrei Leonov, Armin Giese, Margarete Schön, Michael P Schön, Christian Griesinger, Tiago F Outeiro, Donna J Arndt-Jovin, Dorothea Becker
Recent epidemiological and clinical studies have reported a significantly increased risk for melanoma in people with Parkinson's disease. Because no evidence could be obtained that genetic factors are the reason for the association between these two diseases, we hypothesized that of the three major Parkinson's disease-related proteins-α-synuclein, LRRK2, and Parkin-α-synuclein might be a major link. Our data, presented here, demonstrate that α-synuclein promotes the survival of primary and metastatic melanoma cells, which is the exact opposite of the effect that α-synuclein has on dopaminergic neurons, where its accumulation causes neuronal dysfunction and death...
June 20, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28583715/novel-insights-into-the-antioxidant-role-of-tauroursodeoxycholic-acid-in-experimental-models-of-parkinson-s-disease
#6
Alexandra I Rosa, Inês Fonseca, Maria João Nunes, Sara Moreira, Elsa Rodrigues, Andreia Neves Carvalho, Cecília M P Rodrigues, Maria João Gama, Margarida Castro-Caldas
Impaired mitochondrial function and generation of reactive oxygen species are deeply implicated in Parkinson's disease progression. Indeed, mutations in genes that affect mitochondrial function account for most of the familial cases of the disease, and postmortem studies in sporadic PD patients brains revealed increased signs of oxidative stress. Moreover, exposure to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a mitochondrial complex I inhibitor, leads to clinical symptoms similar to sporadic PD. The bile acid tauroursodeoxycholic acid (TUDCA) is an anti-apoptotic molecule shown to protect against MPTP-induced neurodegeneration in mice, but the mechanisms involved are still incompletely identified...
June 2, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28573674/overexpression-of-%C3%AE-synuclein-in-an-astrocyte-cell-line-promotes-autophagy-inhibition-and-apoptosis
#7
Adolfo Garcia Erustes, Fernanda Yakel Stefani, Juliana Yoshie Terashima, Roberta Sessa Stilhano, Priscila Totarelli Monteforte, Gustavo José da Silva Pereira, Sang Won Han, Andrana Karla Calgarotto, Yi-Te Hsu, Rodrigo Portes Ureshino, Cláudia Bincoletto, Soraya Soubhi Smaili
α-Synuclein is the major component of neuronal cytoplasmic aggregates called Lewy bodies, the main pathological hallmark of Parkinson disease. Although neurons are the predominant cells expressing α-synuclein in the brain, recent studies have demonstrated that primary astrocytes in culture also express α-synuclein and regulate α-synuclein trafficking. Astrocytes have a neuroprotective role in several detrimental brain conditions; we therefore analyzed the effects of the overexpression of wild-type α-synuclein and its A30P and A53T mutants on autophagy and apoptosis...
June 2, 2017: Journal of Neuroscience Research
https://www.readbyqxmd.com/read/28571531/c-abl-inhibition-a-novel-therapeutic-target-for-parkinson-s-disease
#8
Abdelrahman Ibrahim Abushouk, Ahmed Negida, Rasha Abdelsalam Elshenawy, Hossam Zein, Ali M Hammad, Ahmed Menshawy, Wael M Y Mohamed
Parkinson's disease (PD) is the most prevalent movement disorder in the world. The major pathological hallmarks of PD are death of dopaminergic neurons and the formation of Lewy bodies. To the moment, there is no cure for PD; current treatments are symptomatic. Investigators are searching for neuroprotective agents and disease modifying strategies to slow the progress of PD. However, due to ignorance of the main pathological sequence of PD, many drug targets failed recently to provide neuroprotective effects in human trials...
June 1, 2017: CNS & Neurological Disorders Drug Targets
https://www.readbyqxmd.com/read/28541509/evidence-that-phosphorylated-ubiquitin-signaling-is-involved-in-the-etiology-of-parkinson-s-disease
#9
Kahori Shiba-Fukushima, Kei-Ichi Ishikawa, Tsuyoshi Inoshita, Nana Izawa, Masashi Takanashi, Shigeto Sato, Osamu Onodera, Wado Akamatsu, Hideyuki Okano, Yuzuru Imai, Nobutaka Hattori
The ubiquitin (Ub) kinase PINK1 and the E3 Ub ligase Parkin, two gene products associated with young-onset Parkinson's disease (PD), participate in mitochondrial quality control. The phosphorylation of mitochondrial polyUb by PINK1, which is activated in a mitochondrial membrane potential (ΔΨm)-dependent manner, facilitates the mitochondrial translocation and concomitant enzymatic activation of Parkin, leading to the clearance of phospho-polyUb-tagged mitochondria via mitophagy. Thus, Ub phosphorylation is a key event in PINK1-Parkin-mediated mitophagy...
May 25, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28526446/thymoquinone-exerts-neuroprotective-effect-in-animal-model-of-parkinson-s-disease
#10
Seyedeh Shohreh Ebrahimi, Shahrbanoo Oryan, Esmael Izadpanah, Kambiz Hassanzadeh
Oxidative stress plays an important role in both the initiation and progression of Parkinson's disease (PD). Rotenone, an environmental toxin, induces oxidative stress and impact mitochondrial dynamics, including fission and fusion. Thymoquinone (TQ) has been reported to have antioxidant and anti-inflammatory characteristics in vitro and in vivo. TQ scavenges free radicals so prevents cell damage against oxidative agents. To evaluate the efficacy of TQ in the management of PD, male Wistar rats (8-10 months) received rotenone...
July 5, 2017: Toxicology Letters
https://www.readbyqxmd.com/read/28523222/olfaction-in-parkin-carriers-in-chinese-patients-with-parkinson-disease
#11
Ying Wang, Jian-Jun Wu, Feng-Tao Liu, Kui Chen, Chen Chen, Su-Shan Luo, Yi-Xuan Wang, Da-Ke Li, Rong-Yuan Guan, Yu-Jie Yang, Yu An, Jian Wang, Yi-Min Sun
BACKGROUND: Olfactory identification was reported to be better among PD (Parkinson disease) patients with Parkin mutations, but previous studies didn't eliminate the interference of other PD related genes on olfaction, and whether olfaction of Parkin mutations patients was better in Chinese population was still unknown. OBJECTIVE: To assess olfaction function among PD patients with Parkin mutations in Chinese population. MATERIALS AND METHODS: A total of 226 PD patients with a positive family history or an early-onset age (<50 years) were enrolled for genetic testing of PD related genes by target sequencing and multiple ligation-dependent probe amplification...
May 2017: Brain and Behavior
https://www.readbyqxmd.com/read/28511254/genetic-forms-of-parkinson-s-disease
#12
Christine Y Kim, Roy N Alcalay
One of the greatest advances in Parkinson's disease (PD) research in the past two decades has been a better understanding of PD genetics. Of the many candidate genes investigated, the best studied include LRRK2, SNCA, VPS35, Parkin, PINK1, and DJ1. The authors review the key clinical features of these monogenic forms, as well as for the prevalent risk factor gene, GBA, including the phenotype, clinical course, and treatment response. They also outline areas for future investigation: longitudinal studies of PD's clinical course, the identification of its premotor manifestations, and its specific mechanisms of pathogenicity...
April 2017: Seminars in Neurology
https://www.readbyqxmd.com/read/28507507/pink1-parkin-dependent-mitochondrial-surveillance-from-pleiotropy-to-parkinson-s-disease
#13
REVIEW
Francois Mouton-Liger, Maxime Jacoupy, Jean-Christophe Corvol, Olga Corti
Parkinson's disease (PD) is one of the most frequent neurodegenerative disease caused by the preferential, progressive degeneration of the dopaminergic (DA) neurons of the substantia nigra (SN) pars compacta. PD is characterized by a multifaceted pathological process involving protein misfolding, mitochondrial dysfunction, neuroinflammation and metabolism deregulation. The molecular mechanisms governing the complex interplay between the different facets of this process are still unknown. PARK2/Parkin and PARK6/PINK1, two genes responsible for familial forms of PD, act as a ubiquitous core signaling pathway, coupling mitochondrial stress to mitochondrial surveillance, by regulating mitochondrial dynamics, the removal of damaged mitochondrial components by mitochondria-derived vesicles, mitophagy, and mitochondrial biogenesis...
2017: Frontiers in Molecular Neuroscience
https://www.readbyqxmd.com/read/28502045/a-clinical-and-molecular-genetic-study-of-50-families-with-autosomal-recessive-parkinsonism-revealed-known-and-novel-gene-mutations
#14
Shaghayegh Taghavi, Rita Chaouni, Abbas Tafakhori, Luis J Azcona, Saghar Ghasemi Firouzabadi, Mir Davood Omrani, Javad Jamshidi, Babak Emamalizadeh, Gholam Ali Shahidi, Mona Ahmadi, Seyed Amir Hassan Habibi, Azadeh Ahmadifard, Atena Fazeli, Marzieh Motallebi, Peyman Petramfar, Saeed Askarpour, Shiva Askarpour, Hossein Ali Shahmohammadibeni, Neda Shahmohammadibeni, Hajar Eftekhari, Amir Ehtesham Shafiei Zarneh, Saeed Mohammadihosseinabad, Mehdi Khorrami, Safa Najmi, Ahmad Chitsaz, Parasto Shokraeian, Hossein Ehsanbakhsh, Jalal Rezaeidian, Reza Ebrahimi Rad, Faranak Madadi, Monavvar Andarva, Elham Alehabib, Minoo Atakhorrami, Seyed Erfan Mortazavi, Zahra Azimzadeh, Mahdis Bayat, Amir Mohammad Besharati, Mohammad Ali Harati-Ghavi, Samareh Omidvari, Zahra Dehghani-Tafti, Faraz Mohammadi, Banafsheh Mohammad Hossein Pour, Hamid Noorollahi Moghaddam, Ehsan Esmaili Shandiz, Arman Habibi, Zahra Taherian-Esfahani, Hossein Darvish, Coro Paisán-Ruiz
In this study, the role of known Parkinson's disease (PD) genes was examined in families with autosomal recessive (AR) parkinsonism to assist with the differential diagnosis of PD. Some families without mutations in known genes were also subject to whole genome sequencing with the objective to identify novel parkinsonism-related genes. Families were selected from 4000 clinical files of patients with PD or parkinsonism. AR inheritance pattern, consanguinity, and a minimum of two affected individuals per family were used as inclusion criteria...
May 13, 2017: Molecular Neurobiology
https://www.readbyqxmd.com/read/28467897/dopamine-induces-oscillatory-activities-in-human-midbrain-neurons-with-parkin-mutations
#15
Ping Zhong, Zhixing Hu, Houbo Jiang, Zhen Yan, Jian Feng
Locomotor symptoms in Parkinson's disease (PD) are accompanied by widespread oscillatory neuronal activities in basal ganglia. Here, we show that activation of dopamine D1-class receptors elicits a large rhythmic bursting of spontaneous excitatory postsynaptic currents (sEPSCs) in midbrain neurons differentiated from induced pluripotent stem cells (iPSCs) of PD patients with parkin mutations, but not normal subjects. Overexpression of wild-type parkin, but not its PD-causing mutant, abolishes the oscillatory activities in patient neurons...
May 2, 2017: Cell Reports
https://www.readbyqxmd.com/read/28458632/the-monoamine-brainstem-reticular-formation-as-a-paradigm-for-re-defining-various-phenotypes-of-parkinson-s-disease-owing-genetic-and-anatomical-specificity
#16
REVIEW
Stefano Gambardella, Rosangela Ferese, Francesca Biagioni, Carla L Busceti, Rosa Campopiano, Anna M P Griguoli, Fiona Limanaqi, Giuseppe Novelli, Marianna Storto, Francesco Fornai
The functional anatomy of the reticular formation (RF) encompasses a constellation of brain regions which are reciprocally connected to sub-serve a variety of functions. Recent evidence indicates that neuronal degeneration within one of these regions spreads synaptically along brainstem circuitries. This is exemplified by the recruitment of various brainstem reticular nuclei in specific Parkinson's disease (PD) phenotypes, and by retrospective analysis of lethargic post-encephalitic parkinsonism. In fact, the spreading to various monoamine reticular nuclei can be associated with occurrence of specific motor and non-motor symptoms (NMS)...
2017: Frontiers in Cellular Neuroscience
https://www.readbyqxmd.com/read/28445716/trumping-neurodegeneration-targeting-common-pathways-regulated-by-autosomal-recessive-parkinson-s-disease-genes
#17
REVIEW
Laura Scott, Valina L Dawson, Ted M Dawson
Parkinson's disease (PD) is a neurodegenerative movement disorder characterized by the progressive loss of dopaminergic (DA) neurons. Most PD cases are sporadic; however, rare familial forms have been identified. Autosomal recessive PD (ARPD) results from mutations in Parkin, PINK1, DJ-1, and ATP13A2, while rare, atypical juvenile ARPD result from mutations in FBXO7, DNAJC6, SYNJ1, and PLA2G6. Studying these genes and their function has revealed mitochondrial quality control, protein degradation processes, and oxidative stress responses as common pathways underlying PD pathogenesis...
April 23, 2017: Experimental Neurology
https://www.readbyqxmd.com/read/28438176/the-pink1-p-i368n-mutation-affects-protein-stability-and-ubiquitin-kinase-activity
#18
Maya Ando, Fabienne C Fiesel, Roman Hudec, Thomas R Caulfield, Kotaro Ogaki, Paulina Górka-Skoczylas, Dariusz Koziorowski, Andrzej Friedman, Li Chen, Valina L Dawson, Ted M Dawson, Guojun Bu, Owen A Ross, Zbigniew K Wszolek, Wolfdieter Springer
BACKGROUND: Mutations in PINK1 and PARKIN are the most common causes of recessive early-onset Parkinson's disease (EOPD). Together, the mitochondrial ubiquitin (Ub) kinase PINK1 and the cytosolic E3 Ub ligase PARKIN direct a complex regulated, sequential mitochondrial quality control. Thereby, damaged mitochondria are identified and targeted to degradation in order to prevent their accumulation and eventually cell death. Homozygous or compound heterozygous loss of either gene function disrupts this protective pathway, though at different steps and by distinct mechanisms...
April 24, 2017: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/28437683/pink1-and-parkin-emerging-themes-in-mitochondrial-homeostasis
#19
REVIEW
Thomas G McWilliams, Miratul Mk Muqit
The Parkinson's disease (PD)-associated protein kinase, PTEN-induced putative kinase1 (PINK1), and ubiquitin E3 ligase Parkin, function in a common signalling pathway known to regulate mitochondrial network homeostasis and quality control, including mitophagy. The multistep activation of this pathway, as well as an unexpected convergence between the post-translational modifications of ubiquitylation and phosphorylation, has added breadth to our understanding of cellular damage responses during human disease...
April 22, 2017: Current Opinion in Cell Biology
https://www.readbyqxmd.com/read/28435104/drosophila-pink1-and-parkin-loss-of-function-mutants-display-a-range-of-non-motor-parkinson-s-disease-phenotypes
#20
Hannah Julienne, Edgar Buhl, David S Leslie, James J L Hodge
Parkinson's disease (PD) is more commonly associated with its motor symptoms and the related degeneration of dopamine (DA) neurons. However, it is becoming increasingly clear that PD patients also display a wide range of non-motor symptoms, including memory deficits and disruptions of their sleep-wake cycles. These have a large impact on their quality of life, and often precede the onset of motor symptoms, but their etiology is poorly understood. The fruit fly Drosophila has already been successfully used to model PD, and has been used extensively to study relevant non-motor behaviours in other contexts, but little attention has yet been paid to modelling non-motor symptoms of PD in this genetically tractable organism...
August 2017: Neurobiology of Disease
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