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https://www.readbyqxmd.com/read/27834214/motor-neuron-disease-tdp-43-pathology-and-memory-deficits-in-mice-expressing-als-ftd-linked-ubqln2-mutations
#1
Nhat T T Le, Lydia Chang, Irina Kovlyagina, Polymnia Georgiou, Nathaniel Safren, Kerstin E Braunstein, Mark D Kvarta, Adam M Van Dyke, Tara A LeGates, Thomas Philips, Brett M Morrison, Scott M Thompson, Adam C Puche, Todd D Gould, Jeffrey D Rothstein, Philip C Wong, Mervyn J Monteiro
Missense mutations in ubiquilin 2 (UBQLN2) cause ALS with frontotemporal dementia (ALS-FTD). Animal models of ALS are useful for understanding the mechanisms of pathogenesis and for preclinical investigations. However, previous rodent models carrying UBQLN2 mutations failed to manifest any sign of motor neuron disease. Here, we show that lines of mice expressing either the ALS-FTD-linked P497S or P506T UBQLN2 mutations have cognitive deficits, shortened lifespans, and develop motor neuron disease, mimicking the human disease...
November 22, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27723099/new-transgenic-als-ftd-models-on-the-rat-walk-an-editorial-highlight-for-increased-ubqln2-expression-causes-neuron-death-in-transgenic-rats
#2
Judith Stegmüller, Matthis Synofzik
This Editorial highlights a study by Huang and colleagues in the current issue of Journal of Neurochemistry. The authors introduce a novel ALS-FTD (amyotrophic lateral sclerosis-frontotemporal dementia) rat model to explore the role of the UBLQN2 gene that has previously been associated with familial ALS-FTD. Over-expression of ubiquilin 2 in the cortex (CTX) and hippocampus of the rat results in ubiquilin 2 aggregates and neurodegeneration together with cognitive deficits. The new rat model not only gives insight into potential molecular underpinnings of ALS-FTD, but also represents an important new tool for future research and therapeutic approaches...
October 2016: Journal of Neurochemistry
https://www.readbyqxmd.com/read/27703430/early-impairment-of-synaptic-and-intrinsic-excitability-in-mice-expressing-als-dementia-linked-mutant-ubqln2
#3
Daniel Radzicki, Erdong Liu, Han-Xiang Deng, Teepu Siddique, Marco Martina
Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are believed to represent the different outcomes of a common pathogenic mechanism. However, while researchers have intensely studied the involvement of motor neurons in the ALS/FTD syndrome, very little is known about the function of hippocampal neurons, although this area is critical for memory and other cognitive functions. We investigated the electrophysiological properties of CA1 pyramidal cells in slices from 1 month-old UBQLN2(P497H) mice, a recently generated model of ALS/FTD that shows heavy depositions of ubiquilin2-positive aggregates in this brain region...
2016: Frontiers in Cellular Neuroscience
https://www.readbyqxmd.com/read/27480424/c9orf72-and-ubqln2-mutations-are-causes-of-amyotrophic-lateral-sclerosis-in-new-zealand-a-genetic-and-pathologic-study-using-banked-human-brain-tissue
#4
Emma L Scotter, Leon Smyth, J Ames W T Bailey, Chun-Hao Wong, Martina de Majo, Caroline A Vance, Beth J Synek, Clinton Turner, Jennifer Pereira, Alison Charleston, Henry J Waldvogel, Maurice A Curtis, Mike Dragunow, Christopher E Shaw, Bradley N Smith, Richard L M Faull
Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease, which causes progressive and eventually fatal loss of motor function. Here, we describe genetic and pathologic characterization of brain tissue banked from 19 ALS patients over nearly 20 years at the Department of Anatomy and the Centre for Brain Research, University of Auckland, New Zealand. We screened for mutations in SOD1, TARDBP, FUS, and C9ORF72 genes and for neuropathology caused by phosphorylated TDP-43, dipeptide repeats (DPRs), and ubiquilin...
July 5, 2016: Neurobiology of Aging
https://www.readbyqxmd.com/read/27477512/ubqln2-mediates-autophagy-independent-protein-aggregate-clearance-by-the-proteasome
#5
Roland Hjerpe, John S Bett, Matthew J Keuss, Alexandra Solovyova, Thomas G McWilliams, Clare Johnson, Indrajit Sahu, Joby Varghese, Nicola Wood, Melanie Wightman, Georgina Osborne, Gillian P Bates, Michael H Glickman, Matthias Trost, Axel Knebel, Francesco Marchesi, Thimo Kurz
Clearance of misfolded and aggregated proteins is central to cell survival. Here, we describe a new pathway for maintaining protein homeostasis mediated by the proteasome shuttle factor UBQLN2. The 26S proteasome degrades polyubiquitylated substrates by recognizing them through stoichiometrically bound ubiquitin receptors, but substrates are also delivered by reversibly bound shuttles. We aimed to determine why these parallel delivery mechanisms exist and found that UBQLN2 acts with the HSP70-HSP110 disaggregase machinery to clear protein aggregates via the 26S proteasome...
August 11, 2016: Cell
https://www.readbyqxmd.com/read/27456931/increased-ubqln2-expression-causes-neuron-death-in-transgenic-rats
#6
Bo Huang, Qinxue Wu, Hongxia Zhou, Cao Huang, Xu-Gang Xia
Pathogenic mutation of ubiquilin 2 (UBQLN2) causes neurodegeneration in amyotrophic lateral sclerosis and frontotemporal lobar degeneration. How UBQLN2 mutations cause the diseases is not clear. While over-expression of UBQLN2 with pathogenic mutation causes neuron death in rodent models, deletion of the Ubqln2 in rats has no effect on neuronal function. Previous findings in animal models suggest that UBQLN2 mutations cause the diseases mainly through a gain rather than a loss of functions. To examine whether the toxic gain in UBQLN2 mutation is related to the enhancement of UBQLN2 functions, we created new transgenic rats over-expressing wild-type human UBQLN2...
October 2016: Journal of Neurochemistry
https://www.readbyqxmd.com/read/27400686/from-animal-models-to-human-disease-a-genetic-approach-for-personalized-medicine-in-als
#7
REVIEW
Vincent Picher-Martel, Paul N Valdmanis, Peter V Gould, Jean-Pierre Julien, Nicolas Dupré
Amyotrophic Lateral Sclerosis (ALS) is the most frequent motor neuron disease in adults. Classical ALS is characterized by the death of upper and lower motor neurons leading to progressive paralysis. Approximately 10 % of ALS patients have familial form of the disease. Numerous different gene mutations have been found in familial cases of ALS, such as mutations in superoxide dismutase 1 (SOD1), TAR DNA-binding protein 43 (TDP-43), fused in sarcoma (FUS), C9ORF72, ubiquilin-2 (UBQLN2), optineurin (OPTN) and others...
July 11, 2016: Acta Neuropathologica Communications
https://www.readbyqxmd.com/read/27164932/comparative-interactomics-analysis-of-different-als-associated-proteins-identifies-converging-molecular-pathways
#8
Anna M Blokhuis, Max Koppers, Ewout J N Groen, Dianne M A van den Heuvel, Stefano Dini Modigliani, Jasper J Anink, Katsumi Fumoto, Femke van Diggelen, Anne Snelting, Peter Sodaar, Bert M Verheijen, Jeroen A A Demmers, Jan H Veldink, Eleonora Aronica, Irene Bozzoni, Jeroen den Hertog, Leonard H van den Berg, R Jeroen Pasterkamp
Amyotrophic lateral sclerosis (ALS) is a devastating neurological disease with no effective treatment available. An increasing number of genetic causes of ALS are being identified, but how these genetic defects lead to motor neuron degeneration and to which extent they affect common cellular pathways remains incompletely understood. To address these questions, we performed an interactomic analysis to identify binding partners of wild-type (WT) and ALS-associated mutant versions of ATXN2, C9orf72, FUS, OPTN, TDP-43 and UBQLN2 in neuronal cells...
August 2016: Acta Neuropathologica
https://www.readbyqxmd.com/read/26969274/mapk13-is-preferentially-expressed-in-gynecological-cancer-stem-cells-and-has-a-role-in-the-tumor-initiation
#9
Kazuyo Yasuda, Yoshihiko Hirohashi, Takafumi Kuroda, Akari Takaya, Terufumi Kubo, Takayuki Kanaseki, Tomohide Tsukahara, Tadashi Hasegawa, Tsuyoshi Saito, Noriyuki Sato, Toshihiko Torigoe
Cancer stem-like cells (CSCs)/cancer-initiating cells (CICs) are defined as small subpopulation of cancer cells that are endowed with higher tumor-initiating ability. CSCs/CICs are resistant to standard cancer therapies including chemotherapy and radiotherapy, and they are thus thought to be responsible for cancer recurrence and metastasis. Therefore, elucidation of molecular mechanisms of CSCs/CICs is essential to cure cancer. In this study, we analyzed the gene expression profiles of gynecological CSCs/CICs isolated as aldehyde dehydrogenase high (ALDH(high)) cells, and found that MAPK13, PTTG1IP, CAPN1 and UBQLN2 were preferentially expressed in CSCs/CICs...
April 15, 2016: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/26944018/disturbance-of-proteasomal-and-autophagic-protein-degradation-pathways-by-amyotrophic-lateral-sclerosis-linked-mutations-in-ubiquilin-2
#10
Mayuko Osaka, Daisuke Ito, Norihiro Suzuki
Ubiquilin (UBQLN), a member of the ubiquitin-like (UBL)-ubiquitin-associated (UBA) family, is a dual regulator of both the proteasomal and autophagic branches of the cellular protein degradation system. Mutations in the UBQLN2 gene encoding ubiquilin 2 cause X-linked amyotrophic lateral sclerosis (ALS)/frontotemporal dementia (FTD), and UBQLN2-positive inclusions have been identified in ALS patients with UBQLN2 mutations as well as in cases of both familial and sporadic ALS without UBQLN2 mutations. Compelling evidence links UBQLN2 to disturbance of the protein quality control network in neurons, but the pathomechanisms remain obscure...
April 1, 2016: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/26912063/frontotemporal-dementia-insights-into-the-biological-underpinnings-of-disease-through-gene-co-expression-network-analysis
#11
Raffaele Ferrari, Paola Forabosco, Jana Vandrovcova, Juan A Botía, Sebastian Guelfi, Jason D Warren, Parastoo Momeni, Michael E Weale, Mina Ryten, John Hardy
BACKGROUND: In frontotemporal dementia (FTD) there is a critical lack in the understanding of biological and molecular mechanisms involved in disease pathogenesis. The heterogeneous genetic features associated with FTD suggest that multiple disease-mechanisms are likely to contribute to the development of this neurodegenerative condition. We here present a systems biology approach with the scope of i) shedding light on the biological processes potentially implicated in the pathogenesis of FTD and ii) identifying novel potential risk factors for FTD...
February 24, 2016: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/26877563/ophthalmic-manifestations-of-amyotrophic-lateral-sclerosis-an-american-ophthalmological-society-thesis
#12
Nicholas J Volpe, Joseph Simonett, Amani A Fawzi, Teepu Siddique
PURPOSE: To determine if clinical and histopathologic findings were present in the eyes of patients with amyotrophic lateral sclerosis (ALS) and explore correlations to an animal model of ALS. METHODS: Two patients with ALS were studied histopathologically as well as the retinas of ALS/dementia transgenic mice with dysfunctional ubiquilin2, UBQLN2(P497H). Clinical study 1, an observational, cross-sectional study, was performed using optical coherence tomography (OCT) to obtain and compare mean total macular thickness and average and quadrant specific peripapillary retinal nerve fiber layer (pRNFL) scans from 16 patients with ALS to controls...
2015: Transactions of the American Ophthalmological Society
https://www.readbyqxmd.com/read/26804609/mutational-analysis-of-tbk1-in-taiwanese-patients-with-amyotrophic-lateral-sclerosis
#13
Pei-Chien Tsai, Yi-Chien Liu, Kon-Ping Lin, Yo-Tsen Liu, Yi-Chu Liao, Cheng-Tsung Hsiao, Bing-Wen Soong, Ping-Keung Yip, Yi-Chung Lee
Mutations in the TBK1 gene were just recently identified to cause amyotrophic lateral sclerosis (ALS), and their role in ALS in various populations remains unclear. The aim of this study was to determine the frequency and spectrum of mutations in TBK1 in a Taiwanese ALS cohort of Han Chinese origin. Mutational analyses of TBK1 were carried out by direct nucleotide sequencing in a cohort of 207 unrelated patients with ALS. Among them, the genetic diagnoses of 168 patients remained elusive after mutations in SOD1, C9ORF72, TARDBP, FUS, ATXN2, OPTN, VCP, UBQLN2, SQSTM1, PFN1, HNRNPA1, HNRNPA2B1, MATR3, CHCHD10, and TUBA4A had been excluded...
April 2016: Neurobiology of Aging
https://www.readbyqxmd.com/read/26521126/ubiquilin-2-drives-nf-%C3%AE%C2%BAb-activity-and-cytosolic-tdp-43-aggregation-in-neuronal-cells
#14
Vincent Picher-Martel, Kallol Dutta, Daniel Phaneuf, Gen Sobue, Jean-Pierre Julien
BACKGROUND: Mutations in the gene encoding Ubiquilin-2 (UBQLN2) are linked to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). UBQLN2 plays a central role in ubiquitin proteasome system (UPS) and UBQLN2 mutants can form cytoplasmic aggregates in vitro and in vivo. RESULTS: Here, we report that overexpression of WT or mutant UBQLN2 species enhanced nuclear factor κB (NF-κB) activation in Neuro2A cells. The inhibition of NF-κB stress-mediated activation with SB203580, a p38 MAPK inhibitor, demonstrated a role for MAPK in NF-κB activation by UBQLN2 species...
October 31, 2015: Molecular Brain
https://www.readbyqxmd.com/read/26303000/ubiquilin2-as-a-novel-marker-for-detection-of-urothelial-carcinoma-cells-in-urine
#15
Keiji Shimada, Tomomi Fujii, Yoshihiro Tatsumi, Satoshi Anai, Kiyohide Fujimoto, Noboru Konishi
BACKGROUND: Ubiquilin 2 (UBQLN2), an ubiquitin-related protein, is strongly expressed in urothelial carcinoma cells, in contrast to no or less expression in non-neoplastic cells; it protects cancer cells from reactive oxygen species (ROS)-induced cytotoxicity. In this study, we investigated whether UBQLN2 immunostaining, using liquid-based cytology sample could improve the accuracy of cytological urine diagnosis. METHODS: Two-hundred and forty-five urinary samples, including 143 negative controls and 102 urothelial carcinomas, consisting of 42 low-grade and 60 high-grade urothelial carcinomas, were used for immunocytochemical analysis of UBQLN2...
January 2016: Diagnostic Cytopathology
https://www.readbyqxmd.com/read/26152284/viral-expression-of-als-linked-ubiquilin-2-mutants-causes-inclusion-pathology-and-behavioral-deficits-in-mice
#16
Carolina Ceballos-Diaz, Awilda M Rosario, Hyo-Jin Park, Paramita Chakrabarty, Amanda Sacino, Pedro E Cruz, Zoe Siemienski, Nicolas Lara, Corey Moran, Natalia Ravelo, Todd E Golde, Nikolaus R McFarland
BACKGROUND: UBQLN2 mutations have recently been associated with familial forms of amyotrophic lateral sclerosis (ALS) and ALS-dementia. UBQLN2 encodes for ubiquilin-2, a member of the ubiquitin-like protein family which facilitates delivery of ubiquitinated proteins to the proteasome for degradation. To study the potential role of ubiquilin-2 in ALS, we used recombinant adeno-associated viral (rAAV) vectors to express UBQLN2 and three of the identified ALS-linked mutants (P497H, P497S, and P506T) in primary neuroglial cultures and in developing neonatal mouse brains...
2015: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/26141599/differential-recruitment-of-ubqln2-to-nuclear-inclusions-in-the-polyglutamine-diseases-hd-and-sca3
#17
COMPARATIVE STUDY
Li Zeng, Bo Wang, Sean A Merillat, Eiko N Minakawa, Matthew D Perkins, Biswarathan Ramani, Sara J Tallaksen-Greene, Maria do Carmo Costa, Roger L Albin, Henry L Paulson
Accumulation of mutant polyglutamine proteins in intraneuronal inclusions is a hallmark of polyglutamine diseases. Impairment of protein clearance systems and sequestration of clearance-related proteins into inclusions occur in many protein folding diseases, including polyglutamine diseases. The ubiquitin-binding and proteasome adaptor protein UBQLN2 participates in protein homeostasis and localizes to inclusions in various neurodegenerative diseases. Employing mouse models and human brain tissue of Huntington's disease (HD) and spinocerebellar ataxia type 3 (SCA3), we show that UBQLN2 is selectively recruited to inclusions in HD but not SCA3...
October 2015: Neurobiology of Disease
https://www.readbyqxmd.com/read/26075709/defective-proteasome-delivery-of-polyubiquitinated-proteins-by-ubiquilin-2-proteins-containing-als-mutations
#18
Lydia Chang, Mervyn J Monteiro
Ubiquilin proteins facilitate delivery of ubiquitinated proteins to the proteasome for degradation. Interest in the proteins has been heightened by the discovery that gene mutations in UBQLN2 cause dominant inheritance of amyotrophic lateral sclerosis (ALS). However, the mechanisms by which the mutations cause ALS are not known. Here we report on the underlying defect of ubiquilin-2 proteins containing ALS-linked mutations in affecting proteasome-mediated degradation. We found that overexpression of ubiquilin-2 proteins containing any one of five different ALS mutations slow degradation of Myc, a prototypic proteasome substrate...
2015: PloS One
https://www.readbyqxmd.com/read/25771394/mutational-analysis-of-matr3-in-taiwanese-patients-with-amyotrophic-lateral-sclerosis
#19
Kon-Ping Lin, Pei-Chien Tsai, Yi-Chu Liao, Wei-Ting Chen, Ching-Piao Tsai, Bing-Wen Soong, Yi-Chung Lee
Mutations in the MATR3 gene were just recently identified to cause familial amyotrophic lateral sclerosis, and their role in amyotrophic lateral sclerosis (ALS) in various populations remains unclear. The aim of this study was to determine the frequency and spectrum of mutations in MATR3 in a Taiwanese ALS cohort of Han Chinese origin. Mutational analyses of MATR3 were carried out by direct nucleotide sequencing in a cohort of 207 unrelated patients with ALS. Among them, the genetic diagnoses of 169 patients remained elusive after mutations in SOD1, C9ORF72, TARDBP, FUS, ATXN2, OPTN, VCP, UBQLN2, SQSTM1, PFN1, HNRNPA1, and HNRNPA2B1 had been excluded...
May 2015: Neurobiology of Aging
https://www.readbyqxmd.com/read/25681989/the-distinct-genetic-pattern-of-als-in-turkey-and-novel-mutations
#20
Aslıhan Özoğuz, Özgün Uyan, Güneş Birdal, Ceren Iskender, Ece Kartal, Suna Lahut, Özgür Ömür, Zeynep Sena Agim, Aslı Gündoğdu Eken, Nesli Ece Sen, Pınar Kavak, Ceren Saygı, Peter C Sapp, Pamela Keagle, Yeşim Parman, Ersin Tan, Filiz Koç, Feza Deymeer, Piraye Oflazer, Haşmet Hanağası, Hakan Gürvit, Başar Bilgiç, Hacer Durmuş, Mustafa Ertaş, Dilcan Kotan, Mehmet Ali Akalın, Halil Güllüoğlu, Mehmet Zarifoğlu, Fikret Aysal, Nilgün Döşoğlu, Kaya Bilguvar, Murat Günel, Özlem Keskin, Tahsin Akgün, Hilmi Özçelik, John E Landers, Robert H Brown, A Nazlı Başak
The frequency of amyotrophic lateral sclerosis (ALS) mutations has been extensively investigated in several populations; however, a systematic analysis in Turkish cases has not been reported so far. In this study, we screened 477 ALS patients for mutations, including 116 familial ALS patients from 82 families and 361 sporadic ALS (sALS) cases. Patients were genotyped for C9orf72 (18.3%), SOD1 (12.2%), FUS (5%), TARDBP (3.7%), and UBQLN2 (2.4%) gene mutations, which together account for approximately 40% of familial ALS in Turkey...
April 2015: Neurobiology of Aging
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