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Sarah Morgan, Aleksey Shatunov, William Sproviero, Ashley R Jones, Maryam Shoai, Deborah Hughes, Ahmad Al Khleifat, Andrea Malaspina, Karen E Morrison, Pamela J Shaw, Christopher E Shaw, Katie Sidle, Richard W Orrell, Pietro Fratta, John Hardy, Alan Pittman, Ammar Al-Chalabi
Amyotrophic lateral sclerosis is a progressive neurodegenerative disease of motor neurons. About 25 genes have been verified as relevant to the disease process, with rare and common variation implicated. We used next generation sequencing and repeat sizing to comprehensively assay genetic variation in a panel of known amyotrophic lateral sclerosis genes in 1126 patient samples and 613 controls. About 10% of patients were predicted to carry a pathological expansion of the C9orf72 gene. We found an increased burden of rare variants in patients within the untranslated regions of known disease-causing genes, driven by SOD1, TARDBP, FUS, VCP, OPTN and UBQLN2...
April 18, 2017: Brain: a Journal of Neurology
Dilcan Kotan, Ceren Iskender, Aslıhan Özoğuz Erimiş, A Nazlı Başak
No abstract text is available yet for this article.
September 2016: Noro Psikiyatri Arsivi
Sanjay Yadav, Nishant Singh, Parag P Shah, David A Rowbotham, Danial Malik, Ankita Srivastav, Jai Shankar, Wan L Lam, William W Lockwood, Levi J Beverly
Ubiquilin (UBQLN) proteins are adaptors thought to link ubiquitinated proteins to the proteasome. However, our lab has recently reported a previously unappreciated role for loss of UBQLN in lung cancer progression. In fact, UBQLN genes are lost in over 50% of lung cancer samples examined. However, a reason for the loss of UBQLN has not been proposed, nor has a selective pressure that could lead to deletion of UBQLN been reported. Diesel Exhaust Particles (DEP) are a major concern in the large cities of developing nations and DEP exposed populations are at an increased risk of developing a number of illnesses, including lung cancer...
April 2017: Neoplasia: An International Journal for Oncology Research
Xiao Huang, Shen Shen, Dongsheng Fan
Mutations in the UBQLN2 gene, which encodes a member of the ubiquitin-like protein family (ubiquilin-2), have been identified in patients with dominant X-linked amyotrophic lateral sclerosis (ALS) and ALS with frontotemporal dementia (FTD). We analyzed mutations in the UBQLN2 gene in a Chinese cohort of 515 patients with sporadic ALS (sALS). A novel missense mutation (p.M392V) was detected in one sALS patient. The p.M392V mutation substitutes a highly conserved residue, has not been reported in the population databases, and previously, at the same residue, a missense mutation p...
2017: PloS One
E P McCann, K L Williams, J A Fifita, I S Tarr, J O'Connor, D B Rowe, G A Nicholson, I P Blair
Amyotrophic lateral sclerosis (ALS) is a clinically and genetically heterogeneous fatal neurodegenerative disease. Around 10% of ALS cases are hereditary. ALS gene discoveries have provided most of our understanding of disease pathogenesis. We aimed to describe the genetic landscape of ALS in Australia by assessing 1013 Australian ALS patients for known ALS mutations by direct sequencing, whole exome sequencing or repeat primed polymerase chain reaction. Age of disease onset and disease duration were used for genotype-phenotype correlations...
January 20, 2017: Clinical Genetics
João Massano, Miguel Leão, Carolina Garrett
In the past few years several gene mutations have been identified as causative of the most frequent neurodegenerative dementias (Alzheimer disease and frontotemporal dementia). These advances, along with the complex phenotype-genotype relationships and the costs associated with genetic testing, have often made it difficult for clinicians to decide with regard to a rational plan for the investigation of the genetic etiology of the degenerative dementias. The Centro Hospitalar São João Neurogenetics Group, a multidisciplinary team of Neurologists and Geneticists with special interest in neurogenetic disorders, devised consensus recommendations for the investigation of the genetic etiology of Alzheimer disease and frontotemporal dementia in clinical practice, based on international consensus documents (currently containing partly outdated information) and published scientific evidence on this topic...
October 2016: Acta Médica Portuguesa
G Lin, D Mao, H J Bellen
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder that affects upper and/or lower motor neurons. It usually affects people between the ages of 40-70. The average life expectancy is about 3-5 years after diagnosis and there is no effective cure available. Identification of variants in more than 20 different loci has provided insight into the pathogenic molecular mechanisms mediating disease pathogenesis. In this review, we focus on seven ALS-causing genes: TDP-43, FUS, C9orf72, VCP, UBQLN2, VAPB and SOD-1, which encompass about 90% of the variants causing familial ALS...
2017: Current Topics in Developmental Biology
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
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
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
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...
January 2017: Neurobiology of Aging
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
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
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
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
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
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
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
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
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
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