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https://www.readbyqxmd.com/read/29112159/mir-1224-5p-mediates-mitochondrial-damage-to-affect-silica-induced-pulmonary-fibrosis-by-targeting-becn1
#1
Qiuyun Wu, Tiantian Xu, Yi Liu, Yan Li, Jiali Yuan, Wenxi Yao, Qi Xu, Weiwen Yan, Chunhui Ni
Silicosis is associated with fibroblast proliferation and extracellular matrix deposition in lung tissues. The dysregulation of miR-1224-5p has been implicated in several human cancers; however, the expression and function of miR-1224-5p in silicosis is unknown. The mitochondrial dysfunctions play critical roles in some diseases, but how these processes are regulated in silicosis remains limited. Here, we explored the role of miR-1224-5p in a mouse model of silicosis. We showed that the expression of miR-1224-5p is increased both in lung tissues of silica-induced pulmonary fibrosis and fibroblasts exposed to TGF-β1...
November 7, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/29040870/parkin-absence-accelerates-microtubule-aging-in-dopaminergic-neurons
#2
Daniele Cartelli, Alida Amadeo, Alessandra Maria Calogero, Francesca Vittoria Marialuisa Casagrande, Carmelita De Gregorio, Mariarosa Gioria, Naoko Kuzumaki, Ilaria Costa, Jenny Sassone, Andrea Ciammola, Nobutaka Hattori, Hideyuki Okano, Stefano Goldwurm, Laurent Roybon, Gianni Pezzoli, Graziella Cappelletti
Loss-of-function caused by mutations in the parkin gene (PARK2) lead to early-onset familial Parkinson's disease. Recently, mechanistic studies proved the ability of parkin in regulating mitochondria homeostasis and microtubule (MT) stability. Looking at these systems during aging of PARK2 knockout mice, we found that loss of parkin induced an accelerated (over)acetylation of MT system both in dopaminergic neuron cell bodies and fibers, localized in the substantia nigra and corpus striatum, respectively. Interestingly, in PARK2 knockout mice, changes of MT stability preceded the alteration of mitochondria transport...
September 20, 2017: Neurobiology of Aging
https://www.readbyqxmd.com/read/29020610/neonatal-c57bl-6j-and-parkin-mice-respond-differently-following-developmental-manganese-exposure-result-of-a-high-dose-pilot-study
#3
Melanie L Foster, Thomas B Bartnikas, Hailey C Maresca-Fichter, Courtney Mercadante, Miriam Dash, Chelsea Miller, David C Dorman
It has been suggested that childhood exposure to neurotoxicants may increase the risk of Parkinson's disease (PD) or other neurodegenerative disease in adults. Some recessive forms of PD have been linked to loss-of-function mutations in the Park2 gene that encodes for parkin. The purpose of this pilot study was to evaluate whether responses to neonatal manganese (Mn) exposure differ in mice with a Park2 gene defect (parkin mice) when compared with a wildtype strain (C57BL/6J). Neonatal parkin and C57BL/6J littermates were randomly assigned to 0, 11, or 25mg Mn/kg-day dose groups with oral exposures occurring from postnatal day (PND) 1 through PND 28...
October 8, 2017: Neurotoxicology
https://www.readbyqxmd.com/read/28984592/tomm40-and-apoe-gene-expression-and-cognitive-decline-in-japanese-alzheimer-s-disease-subjects
#4
Ayano Mise, Yuta Yoshino, Kiyohiro Yamazaki, Yuki Ozaki, Tomoko Sao, Taku Yoshida, Takaaki Mori, Yoko Mori, Shinichiro Ochi, Jun-Ichi Iga, Shu-Ichi Ueno
BACKGROUND: TOMM40 is located on chromosome 19, is in linkage disequilibrium with apolipoprotein E (APOE), andis reported in several genome-wide association studies to be associated with Alzheimer's disease (AD). OBJECTIVE: Assess APOE and TOM40 and mitochondrial genes as blood biomarkers for AD. METHODS: We examined TOMM40, PTEN-induced putative kinase 1 (PINK1), Parkin RBR E3 ubiquitin protein ligase (PARK2), and APOE mRNA expression in relation to the methylation rates of CpG sites in the upstream region of TOMM40exon 1 in peripheral leukocytes and TOMM40523 polyT genotypes in 60 AD and age- and sex-matched control subjects...
2017: Journal of Alzheimer's Disease: JAD
https://www.readbyqxmd.com/read/28976966/hippo-pathway-deficiency-reverses-systolic-heart-failure-after-infarction
#5
John P Leach, Todd Heallen, Min Zhang, Mahdis Rahmani, Yuka Morikawa, Matthew C Hill, Ana Segura, James T Willerson, James F Martin
Mammalian organs vary widely in regenerative capacity. Poorly regenerative organs, such as the heart are particularly vulnerable to organ failure. Once established, heart failure commonly results in mortality. The Hippo pathway, a kinase cascade that prevents adult cardiomyocyte proliferation and regeneration, is upregulated in human heart failure. Here we show that deletion of the Hippo pathway component Salvador (Salv) in mouse hearts with established ischaemic heart failure after myocardial infarction induces a reparative genetic program with increased scar border vascularity, reduced fibrosis, and recovery of pumping function compared with controls...
October 12, 2017: Nature
https://www.readbyqxmd.com/read/28959184/mitophagy-failure-in-fibroblasts-and-ipsc-derived-neurons-of-alzheimer-s-disease-associated-presenilin-1-mutation
#6
Patricia Martín-Maestro, Ricardo Gargini, Andrew A Sproul, Esther García, Luis C Antón, Scott Noggle, Ottavio Arancio, Jesús Avila, Vega García-Escudero
Familial Alzheimer's disease (FAD) is clearly related with the accumulation of amyloid-beta (Aβ) and its deleterious effect on mitochondrial function is well established. Anomalies in autophagy have also been described in these patients. In the present work, functional analyses have been performed to study mitochondrial recycling process in patient-derived fibroblasts and neurons from induced pluripotent stem cells harboring the presenilin 1 mutation A246E. Mitophagy impairment was observed due to a diminished autophagy degradation phase associated with lysosomal anomalies, thus causing the accumulation of dysfunctional mitochondria labeled by Parkin RBR E3 ubiquitin protein ligase (PARK2)...
2017: Frontiers in Molecular Neuroscience
https://www.readbyqxmd.com/read/28945247/structural-basis-for-specific-cleavage-of-lys6-linked-polyubiquitin-chains-by-usp30
#7
Yusuke Sato, Kei Okatsu, Yasushi Saeki, Koji Yamano, Noriyuki Matsuda, Ai Kaiho, Atsushi Yamagata, Sakurako Goto-Ito, Minoru Ishikawa, Yuichi Hashimoto, Keiji Tanaka, Shuya Fukai
Parkin ubiquitin (Ub) ligase (also known as PARK2) ubiquitinates damaged mitochondria for their clearance and quality control. USP30 deubiquitinase opposes parkin-mediated Ub-chain formation on mitochondria by preferentially cleaving Lys6-linked Ub chains. Here, we report the crystal structure of zebrafish USP30 in complex with a Lys6-linked diubiquitin (diUb or Ub2) at 1.87-Å resolution. The distal Ub-recognition mechanism of USP30 is similar to those of other USP family members, whereas Phe4 and Thr12 of the proximal Ub are recognized by a USP30-specific surface...
November 2017: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/28928831/park2-negatively-regulates-the-metastasis-and-epithelial-mesenchymal-transition-of-glioblastoma-cells-via-zeb1
#8
Haiyang Wang, Zhenfeng Jiang, Meng Na, Haitao Ge, Chongyang Tang, Hong Shen, Zhiguo Lin
Glioblastoma multiforme (GBM), one of the most aggressive human malignant brain tumors, is induced by multiple complex pathological mechanisms. The main cause of mortality in patients with GBM is the invasion-metastasis cascade of tumor cells. The dysfunction of Parkinson protein 2 E3 ubiquitin protein ligase (PARK2) is closely linked with the development of certain human cancers. However, whether PARK2 is associated with metastasis in GBM remains unknown. The present study demonstrated that the metastasis and invasion of U87 cells were significantly repressed by PARK2 overexpression...
September 2017: Oncology Letters
https://www.readbyqxmd.com/read/28914586/presenilins-at-the-crossroad-of-a-functional-interplay-between-park2-parkin-and-pink1-to-control-mitophagy-implication-for-neurodegenerative-diseases
#9
Frédéric Checler, Thomas Goiran, Cristine Alves da Costa
Autophagic and mitophagic defects are consistently observed in Alzheimer's disease-affected brains. However, the mechanistic defects underlying these anatomical lesions remained unexplained. We have delineated a molecular cascade by which PSEN1 and PSEN2 (presenilins 1 and 2) control PINK1 transcription and function by an AICD-mediated FOXO3a-dependent mechanism. Further, we establish that PARK2 (parkin) acts upstream to PINK1 and regulates its function by a PSEN-dependent mechanism. Our study thus demonstrates a functional interplay between PSEN and PINK1 and establishes a feedback process by which PARK2 and PINK1 could control mitochondrial dysfunction and autophagic processes in various neurodegenerative pathologies including Alzheimer's and Parkinson's diseases...
September 15, 2017: Autophagy
https://www.readbyqxmd.com/read/28913705/variable-park2-mutations-cause-early-onset-parkinson-s-disease-in-a-small-restricted-population
#10
Shay Ben-Shachar, Zaid Afawi, Rafik Masalha, Samih Badarny, Tova Neiman, Dina Pavzner, Anat Bar-Shira, Avi Orr-Urtreger
Early-onset Parkinson's disease (EOPD) is less common than the typical adult-onset PD and may be associated with a genetic etiology. Mutations in several genes are known to cause autosomal recessive (AR) PD. This study aimed to detect the etiology of EOPD in consanguineous families or families living in a specific small geographic region in Israel. Six families with EOPD affecting more than a single individual were recruited. Homozygous mapping analysis using a single-nucleotide polymorphism-based array was performed in all families, followed by Sanger sequencing of related genes based on the mapping results...
October 2017: Journal of Molecular Neuroscience: MN
https://www.readbyqxmd.com/read/28894028/mtorc1-regulates-both-general-autophagy-and-mitophagy-induction-after-oxidative-phosphorylation-uncoupling
#11
Alberto Bartolomé, Ana García-Aguilar, Shun-Ichiro Asahara, Yoshiaki Kido, Carlos Guillén, Utpal B Pajvani, Manuel Benito
The mechanistic target of rapamycin complex 1 (MTORC1) is a critical negative regulator of general autophagy. We hypothesized that MTORC1 may specifically regulate autophagic clearance of damaged mitochondria. To test this, we used cells lacking tuberous sclerosis complex 2 (TSC2 -/-), which show constitutive MTORC1 activation. TSC2 -/- cells show MTORC1-dependent impaired autophagic flux after chemical uncoupling of mitochondria, increased mitochondrial protein aging and accumulation of p62/SQSTM1 positive mitochondria...
September 11, 2017: Molecular and Cellular Biology
https://www.readbyqxmd.com/read/28854370/generation-of-mouse-haploid-somatic-cells-by-small-molecules-for-genome-wide-genetic-screening
#12
Zheng-Quan He, Bao-Long Xia, Yu-Kai Wang, Jing Li, Gui-Hai Feng, Lin-Lin Zhang, Yu-Huan Li, Hai-Feng Wan, Tian-Da Li, Kai Xu, Xue-Wei Yuan, Yu-Fei Li, Xin-Xin Zhang, Ying Zhang, Liu Wang, Wei Li, Qi Zhou
The recent success of derivation of mammalian haploid embryonic stem cells (haESCs) has provided a powerful tool for large-scale functional analysis of the mammalian genome. However, haESCs rapidly become diploidized after differentiation, posing challenges for genetic analysis. Here, we show that the spontaneous diploidization of haESCs happens in metaphase due to mitotic slippage. Diploidization can be suppressed by small-molecule-mediated inhibition of CDK1 and ROCK. Through ROCK inhibition, we can generate haploid somatic cells of all three germ layers from haESCs, including terminally differentiated neurons...
August 29, 2017: Cell Reports
https://www.readbyqxmd.com/read/28843361/germline-mutations-in-dna-repair-genes-in-lung-adenocarcinoma
#13
Erin M Parry, Dustin L Gable, Susan E Stanley, Sara E Khalil, Valentin Antonescu, Liliana Florea, Mary Armanios
INTRODUCTION: Although lung cancer is generally thought to be environmentally provoked, anecdotal familial clustering has been reported, suggesting that there may be genetic susceptibility factors. We systematically tested whether germline mutations in eight candidate genes may be risk factors for lung adenocarcinoma. METHODS: We studied lung adenocarcinoma cases for which germline sequence data had been generated as part of The Cancer Genome Atlas project but had not been previously analyzed...
November 2017: Journal of Thoracic Oncology
https://www.readbyqxmd.com/read/28830306/epigenetic-approach-to-early-onset-parkinson-s-disease-low-methylation-status-of-snca-and-park2-promoter-regions
#14
Isil Ezgi Eryilmaz, Gulsah Cecener, Sevda Erer, Unal Egeli, Berrin Tunca, Mehmet Zarifoglu, Bulent Elibol, Ayse Bora Tokcaer, Esen Saka, Meltem Demirkiran, Cenk Akbostanci, Okan Dogu, Beril Colakoglu, Gulay Kenangil, Hakan Kaleagasi
Background and aim The effect of epigenetic modifications in the genes related to Parkinson's disease (PD) is still unclear. In the present study, we investigated methylation status of SNCA and PARK2 genes in patients with early-onset Parkinson's disease (EOPD). Materials and methods The promoter region methylation status of SNCA and PARK2 genes was evaluated by methylation specific-PCR (MSP) in 91 patients with EOPD and 52 healthy individuals. Results The methylation of SNCA and PARK2 promoter regions were significantly lower in EOPD patients compared to the control group (P = 0...
August 22, 2017: Neurological Research
https://www.readbyqxmd.com/read/28826884/reduced-expression-of-park2-in-manganese-exposed-smelting-workers
#15
Ximin Fan, Ying Luo, Qiyuan Fan, Wei Zheng
Manganese (Mn) is widely used in modern industries. Occupational exposure to Mn is known to cause clinical syndromes similar, but not identical to, Parkinson's disease. This human cohort study was designed to investigate if workers exposed to Mn altered the PARK2 gene expression, leading to Mn-induced neurotoxicity. Workers (n=26) occupationally exposed to Mn were recruited from a Mn-iron (Fe) alloy smelter, and control workers (n=20) without Mn-exposure were from an Fe smelter from Zunyi City in China. Subjects were matched with socioeconomic status and background for environmental factors...
September 2017: Neurotoxicology
https://www.readbyqxmd.com/read/28820284/bnip3l-nix-mediated-mitophagy-protects-against-ischemic-brain-injury-independent-of-park2
#16
Yang Yuan, Yanrong Zheng, Xiangnan Zhang, Ying Chen, Xiaoli Wu, Jiaying Wu, Zhe Shen, Lei Jiang, Lu Wang, Wei Yang, Jianhong Luo, Zhenghong Qin, Weiwei Hu, Zhong Chen
Cerebral ischemia induces massive mitochondrial damage. These damaged mitochondria are cleared, thus attenuating brain injury, by mitophagy. Here, we identified the involvement of BNIP3L/NIX in cerebral ischemia-reperfusion (I-R)-induced mitophagy. Bnip3l knockout (bnip3l(-/-)) impaired mitophagy and aggravated cerebral I-R injury in mice, which can be rescued by BNIP3L overexpression. The rescuing effects of BNIP3L overexpression can be observed in park2(-/-) mice, which showed mitophagy deficiency after I-R...
October 3, 2017: Autophagy
https://www.readbyqxmd.com/read/28812939/removing-dysfunctional-mitochondria-from-axons-independent-of-mitophagy-under-pathophysiological-conditions
#17
Mei-Yao Lin, Xiu-Tang Cheng, Yuxiang Xie, Qian Cai, Zu-Hang Sheng
Chronic mitochondrial dysfunction has been implicated in major neurodegenerative diseases. Long-term cumulative pathological stress leads to axonal accumulation of damaged mitochondria. Therefore, the early removal of defective mitochondria from axons constitutes a critical step of mitochondrial quality control. We recently investigated the axonal mitochondrial response to mild stress in wild-type neurons and chronic mitochondrial defects in amyotrophic lateral sclerosis (ALS)- and Alzheimer disease (AD)-linked neurons...
October 3, 2017: Autophagy
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
#18
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/28744025/genetic-loci-associated-with-an-earlier-age-at-onset-in-multiplex-schizophrenia
#19
Annemarie L Woolston, Po-Chang Hsiao, Po-Hsiu Kuo, Shi-Heng Wang, Yin-Ju Lien, Chih-Min Liu, Hai-Gwo Hwu, Tzu-Pin Lu, Eric Y Chuang, Li-Ching Chang, Chien-Hsiun Chen, Jer-Yuarn Wu, Ming T Tsuang, Wei J Chen
An earlier age at onset (AAO) has been associated with greater genetic loadings in schizophrenia. This study aimed to identify modifier loci associated with an earlier AAO of schizophrenia. A genome-wide association analysis (GWAS) was conducted in 94 schizophrenia probands with the earliest AAO and 91 with the latest AAO. Candidate single nucleotide polymorphisms (SNPs) were then genotyped in the co-affected siblings and unrelated probands. Multi-SNP genetic risk scores (GRS) composed of the candidate loci were used to distinguish patients with an early or late AAO...
July 25, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28716221/parkin-mutation-may-be-associated-with-serious-akinesia-in-a-patient-with-parkinson-s-disease
#20
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
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