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https://www.readbyqxmd.com/read/28733540/am1241-alleviates-mptp-induced-parkinson-s-disease-and-promotes-the-regeneration-of-da-neurons-in-pd-mice
#1
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
#2
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
#3
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
#4
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
#5
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
#6
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
#7
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
#8
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, e.g., 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...
June 29, 2017: European Journal of Neuroscience
https://www.readbyqxmd.com/read/28656059/parkin-knockout-inhibits-neuronal-development-via-regulation-of-proteasomal-degradation-of-p21
#9
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
#10
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
#11
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
#12
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
#13
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
#14
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
#15
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 post mortem 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...
June 3, 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
#16
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
#17
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
#18
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
#19
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
#20
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
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