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Christopher P Webster, Emma F Smith, Andrew J Grierson, Kurt J De Vos
A GGGGCC hexanucleotide repeat expansion in the first intron of the C9orf72 gene is the most common genetic defect associated with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) (C9ALS/FTD). Haploinsufficiency and a resulting loss of C9orf72 protein function has been suggested as a possible pathogenic mechanism in C9ALS/FTD. C9ALS/FTD patients exhibit specific ubiquitin and p62/sequestosome-1 positive but TDP-43 negative inclusions in the cerebellum and hippocampus, indicating possible autophagy deficits in these patients...
October 21, 2016: Small GTPases
Francesca Lupo, Elena Tibaldi, Alessandro Matte, Alok K Sharma, Anna Maria Brunati, Seth L Alper, Carlo Zancanaro, Donatella Benati, Angela Siciliano, Mariarita Bertoldi, Francesca Zonti, Alexander Storch, Ruth H Walker, Adrian Danek, Benedikt Bader, Andreas Hermann, Lucia De Franceschi
Chorea-acanthocytosis is one of the hereditary neurodegenerative disorders known as the neuroacanthocytoses. Chorea-acanthocytosis is characterized by circulating acanthocytes deficient in chorein, a protein of unknown function. We report here for the first time that chorea-acanthocytosis red-cells are characterized by impaired autophagy, with cytoplasmic accumulation of active Lyn and of autophagy-related proteins Ulk1, Atg7. In chorea-acanthocytosis erythrocytes, active Lyn is sequestered by HSP90-70 to form high-molecular-weight complexes that stabilize and protect Lyn from its proteasomal degradation, contributing to toxic Lyn accumulation...
October 14, 2016: Blood
Zhen-Hua Chen, Wen-Tao Wang, Wei Huang, Ke Fang, Yu-Meng Sun, Shu-Rong Liu, Xue-Qun Luo, Yue-Qin Chen
Increasing evidence has indicated that long noncoding RNAs (lncRNAs) are of great importance in different cell contexts. However, only a very small number of lncRNAs have been experimentally validated and functionally annotated during human hematopoiesis. Here, we report an lncRNA, HOTAIRM1, which is associated with myeloid differentiation and has pivotal roles in the degradation of oncoprotein PML-RARA and in myeloid cell differentiation by regulating autophagy pathways. We first revealed that HOTAIRM1 has different variants that are expressed at different levels in cells and that the expression pattern of HOTAIRM1 is closely related to that of the PML-RARA oncoprotein in acute promyelocytic leukemia (APL) patients...
October 14, 2016: Cell Death and Differentiation
Claudia Manzoni, Adamantios Mamais, Dorien A Roosen, Sybille Dihanich, Marc P M Soutar, Helene Plun-Favreau, Rina Bandopadhyay, John Hardy, Sharon A Tooze, Mark R Cookson, Patrick A Lewis
Leucine rich repeat kinase 2 is a complex enzyme with both kinase and GTPase activities, closely linked to the pathogenesis of several human disorders including Parkinson's disease, Crohn's disease, leprosy and cancer. LRRK2 has been implicated in numerous cellular processes; however its physiological function remains unclear. Recent reports suggest that LRRK2 can act to regulate the cellular catabolic process of macroautophagy, although the precise mechanism whereby this occurs has not been identified. To investigate the signalling events through which LRRK2 acts to influence macroautophagy, the mammalian target of rapamycin (mTOR)/Unc-51-like kinase 1 (ULK1) and Beclin-1/phosphatidylinositol 3-kinase (PI3K) pathways were evaluated in astrocytic cell models in the presence and absence of LRRK2 kinase inhibitors...
October 12, 2016: Scientific Reports
Qing-Hua Cao, Fang Liu, Zu-Li Yang, Xin-Hui Fu, Zi-Huan Yang, Quentin Liu, Lei Wang, Xiang-Bo Wan, Xin-Juan Fan
Autophagy-related (ATG) genes contributed to tumorigenesis and cancer progression. This study aims to investigate the expression of ATG proteins and their clinicopathological significance in gastric cancer. Nine well-known ATG proteins, (ULK1, Beclin 1, ATG3, ATG5, ATG7, ATG9, ATG10, ATG12 and LC3B) and p62/SQSTM1, which represented key regulators that participated in whole autophagosomes stepwise processes, were detected in a large cohort of 352 primary gastric cancer patients. Among these 352 patients, 117 cases were randomly assigned to the training set to detect the clinicopathological value of ATG proteins, and another 235 patients were used as the testing set for further validation...
2016: American Journal of Translational Research
Christopher R Braden, Thomas P Neufeld
Although canonical autophagy regulation requires a multi-protein complex centered on the Ser/Thr-kinase Atg1 (mammalian Ulk1/2), alternative signals can induce autophagy independent of Atg1 through unknown mechanisms. Here we identify the Drosophila Ulk3 ortholog, another Drosophila Unc-51-like kinase (ADUK), as an Atg1-independent autophagy inducer. ADUK interacts with Atg1 complex members Atg13 and 200 kDa FAK family kinase-interacting protein, and requires Atg13 but not Atg1 for autophagy induction. Loss of ADUK shortens adult lifespan and reduces the autophagic response to a chemical stressor, dimethyl sulfoxide...
September 22, 2016: FEBS Journal
Alejandro Romero, Eva Ramos, Irma Ares, Víctor Castellano, Marta Martínez, María-Rosa Martínez-Larrañaga, Arturo Anadón, María-Aránzazu Martínez
In this study, we investigated the induction of oxidative stress and apoptosis in human neuroblastoma cell line SH-SY5Y in response to alpha-cypermethrin (α-CYPER) exposure. MTT and LDH assays were carried out to assess the α-CYPER cytotoxicity. The IC50 value for α-CYPER was calculated to be 78.3 ± 2.98 µM for the MTT assay and 71.5 ± 3.94 µM for LDH assay. The pyrethroid α-CYPER (1-100 µM), in a dose-dependent manner, induced a significant increase in lipid peroxides measured as malondialdehyde (MDA) and in the levels of nitric oxide (NO)...
October 4, 2016: Archives of Toxicology
Qianqian Zhao, Zhaopeng Wang, Zhaoxia Wang, Licun Wu, Weidong Zhang
Aspirin is known to have inhibitory effects on growth development in various types of tumor. In previous studies, it was observed to inhibit angiogenesis by downregulating the expression of vascular endothelial growth factor-A (VEGF-A). In the present study, murine H22 hepatocarcinoma and S180 sarcoma models were used to ascertain whether aspirin could inhibit angiogenesis and promote autophagy in tumors. Tumor-bearing mice were randomly divided into four groups with 10 mice per group: i) no treatment; ii) low-dose aspirin (100 mg/kg); iii) high-dose aspirin (400 mg/kg); iv) everolimus group (4 mg/kg)...
October 2016: Oncology Letters
Subhadip Mukhopadhyay, Prajna Paramita Naik, Prashanta Kumar Panda, Niharika Sinha, Durgesh Nandini Das, Sujit Kumar Bhutia
Mitophagy is a highly specialised type of autophagy that plays an important role in regulating mitochondrial dynamics and controls cellular quality during stress. In this study, we established that serum starvation led to induction of cellular inhibitor of apoptosis protein-1 (cIAP1), which regulates mitophagy through ubiquitination. Importantly, gain and loss of function of cIAP1 resulted in concomitant alteration in mitophagy confirming the direct implication of cIAP1 in induction of mitophagy. Interestingly, it was observed that cIAP1 translocated to mitochondria to associate with TOM20, Ulk1, and LC3 to initiate mitophagy...
October 28, 2016: Biochemical and Biophysical Research Communications
Santosh Chauhan, Suresh Kumar, Ashish Jain, Marisa Ponpuak, Michal H Mudd, Tomonori Kimura, Seong Won Choi, Ryan Peters, Michael Mandell, Jack-Ansgar Bruun, Terje Johansen, Vojo Deretic
Selective autophagy performs an array of tasks to maintain intracellular homeostasis, sterility, and organellar and cellular functionality. The fidelity of these processes depends on precise target recognition and limited activation of the autophagy apparatus in a localized fashion. Here we describe cooperation in such processes between the TRIM family and Galectin family of proteins. TRIMs, which are E3 ubiquitin ligases, displayed propensity to associate with Galectins. One specific TRIM, TRIM16, interacted with Galectin-3 in a ULK1-dependent manner...
October 10, 2016: Developmental Cell
José M Rodríguez-Vargas, María I Rodríguez, Jara Majuelos-Melguizo, Ángel García-Diaz, Ariannys González-Flores, Abelardo López-Rivas, László Virág, Giuditta Illuzzi, Valerie Schreiber, Françoise Dantzer, F Javier Oliver
AMPK is a central energy sensor linking extracellular milieu fluctuations with the autophagic machinery. In the current study we uncover that Poly(ADP-ribosyl)ation (PARylation), a post-translational modification (PTM) of proteins, accounts for the spatial and temporal regulation of autophagy by modulating AMPK subcellular localisation and activation. More particularly, we show that the minority AMPK pool needs to be exported to the cytosol in a PARylation-dependent manner for optimal induction of autophagy, including ULK1 phosphorylation and mTORC1 inactivation...
September 30, 2016: Cell Death and Differentiation
Jose J G Marin, Elisa Lozano, Maria J Perez
Alterations in mitochondrial DNA (mtDNA) and autophagy activation are common events in tumors. Here we have investigated the effect of mitochondrial genome depletion on chemical hypoxia-induced autophagy in liver tumor cells. Human SK-Hep-1 wild-type and mtDNA-depleted (Rho) cells were exposed to the hypoxia mimetic agents CoCl2 and deferoxamine (DFO). Up-regulation of HIF-1α, but not HIF-2α was observed. The expression of several HIF-1α target genes was also found. In human SK-Hep-1 and mouse Hepa 1-6 liver tumor cells, but not in the counterpart Rho derived lines, chemical hypoxia increased the abundance of autophagosomes and autolysosomes...
September 26, 2016: Free Radical Biology & Medicine
Hong-Yi Zhang, Ya-Dong Ma, Ye Zhang, Jie Cui, Zi-Ming Wang
AIM: To evaluate the expression levels and prognostic significance of autophagy-related markers, UNC-51-like kinase1 (ULK1), Beclin1, microtubule-associated protein light chain 3 (LC3), autophagy-related gene 5 (ATG5) and mitochondrion-associated autophagy inhibitor, LRPPRC, in patients with metastatic prostate cancer (PCa) after androgen deprivation therapy (ADT). METHODS: Expressions of ULK1, Beclin1, LC3, ATG5 and LRPPRC were assessed by immunohistochemical examination in 198 patients with metastatic PCa who were receiving ADT (goserelin and bicalutamide)...
September 27, 2016: Journal of Clinical Pathology
Satoru Torii, Tatsushi Yoshida, Satoko Arakawa, Shinya Honda, Akira Nakanishi, Shigeomi Shimizu
Autophagy is an evolutionary conserved process that degrades subcellular constituents. Unlike starvation-induced autophagy, the molecular mechanism of genotoxic stress-induced autophagy has not yet been fully elucidated. In this study, we analyze the molecular mechanism of genotoxic stress-induced autophagy and identify an essential role of dephosphorylation of the Unc51-like kinase 1 (Ulk1) at Ser(637), which is catalyzed by the protein phosphatase 1D magnesium-dependent delta isoform (PPM1D). We show that after exposure to genotoxic stress, PPM1D interacts with and dephosphorylates Ulk1 at Ser(637) in a p53-dependent manner...
September 26, 2016: EMBO Reports
Abhishek Kumar Singh, Mahendra Pratap Kashyap, Vinay Kumar Tripathi, Sandeep Singh, Geetika Garg, Syed Ibrahim Rizvi
Autophagy is a catabolic process involved in the continuous removal of toxic protein aggregates and cellular organelles to maintain the homeostasis and functional integrity of cells. The mechanistic understanding of autophagy mediated neuroprotection during the development of neurodegenerative disorders remains elusive. Here, we investigated the potential role of rapamycin-induced activation of autophagy and PI3K/Akt1/mTOR/CREB pathway(s) in the neuroprotection of amyloid-beta (Aβ1-42)-insulted hippocampal neurons in rat model of Alzheimer's disease (AD) like phenotypes...
September 22, 2016: Molecular Neurobiology
Sukriti Krishan, Des R Richardson, Sumit Sahni
Adenosine monophosphate-activated protein kinase (AMPK) is a cellular energy sensor that monitors ATP levels. There is also evidence that AMPK has onco-suppressive properties. Iron plays a crucial role in cellular energy transducing pathways and tumor cell proliferation. Therefore, metals (e.g., iron) could play an important role in the regulation of AMPK-dependent pathways. Hence, this investigation examined the effect of the iron and copper chelator and potent anti-cancer agent, di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone (Dp44mT), on the AMPK-mediated pathway...
September 15, 2016: Biochimica et Biophysica Acta
Ammar Kurdi, Mireille De Doncker, Arthur Leloup, Hugo Neels, Jean-Pierre Timmermans, Katrien Lemmens, Sandra Apers, Guido R Y De Meyer, Wim Martinet
BACKGROUND AND PURPOSE: Everolimus is an allosteric inhibitor of the mechanistic target of rapamycin complex 1 (mTORC1) widely known for its potent autophagy stimulating properties. Because everolimus shows poor solubility and stability in aqueous solutions, long-term in vivo administration in preclinical models is challenging. The aim of the present study was to evaluate the effects of short-term and long-term everolimus administration on mTORC1 inhibition and autophagy induction in mice...
September 16, 2016: British Journal of Pharmacology
Giulia Allavena, Caroline Boyd, Kyaw Soe Oo, Emilia Maellaro, Boris Zhivotovsky, Vitaliy O Kaminskyy
Macroautophagy/autophagy is a well-organized process of intracellular degradation, which is rapidly activated under starvation conditions. Recent data demonstrate a transcriptional upregulation of several autophagy genes as a mechanism that controls autophagy in response to starvation. Here we report that despite the significant upregulation of mRNA of the essential autophagy initiation gene ULK1, its protein level is rapidly reduced under starvation. Although both autophagic and proteasomal systems contribute to the degradation of ULK1, under prolonged nitrogen deprivation, its level was still reduced in ATG7 knockout cells, and only initially stabilized in cells treated with the lysosomal or proteasomal inhibitors...
September 14, 2016: Autophagy
Mei Yang, Chen Liang, Kunchithapadam Swaminathan, Stephanie Herrlinger, Fan Lai, Ramin Shiekhattar, Jian-Fu Chen
The intronic GGGGCC hexanucleotide repeat expansion in chromosome 9 open reading frame 72 (C9ORF72) is a prevalent genetic abnormality identified in both frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Smith-Magenis syndrome chromosomal region candidate gene 8 (SMCR8) is a protein with unclear functions. We report that C9ORF72 is a component of a multiprotein complex containing SMCR8, WDR41, and ATG101 (an important regulator of autophagy). The C9ORF72 complex displays guanosine triphosphatase (GTPase) activity and acts as a guanosine diphosphate-guanosine 5'-triphosphate (GDP-GTP) exchange factor (GEF) for RAB39B...
September 2016: Science Advances
Gholamreza Fazeli, Michaela Trinkwalder, Linda Irmisch, Ann Marie Wehman
In animals, the midbody coordinates the end of cytokinesis when daughter cells separate through abscission. The midbody was thought to be sequestered by macroautophagy, but recent evidence suggests that midbodies are primarily released and phagocytosed. It was unknown, however, whether autophagy proteins play a role in midbody phagosome degradation. Using a protein degradation assay, we show that midbodies are released in Caenorhabditis elegans Released midbodies are known to be internalized by actin-driven phagocytosis, which we show requires the RAB-5 GTPase to localize the class III phosphoinositide 3-kinase (PI3K) complex at the cortex...
October 15, 2016: Journal of Cell Science
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