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UBQLN2

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https://www.readbyqxmd.com/read/29547719/ubiquilin-2-shuttling-clients-out-of-phase
#1
Ipsita Subudhi, James Shorter
Ubiquilin 2 (UBQLN2) is an amyotrophic lateral sclerosis-linked molecular chaperone with a prion-like domain that directly engages ubiquitin to triage clients for proteasomal degradation. Dao et al. (2018) now establish that UBQLN2 forms ubiquitin-labile liquids, which may enable UBQLN2 to specifically extract ubiquitylated clients from stress granules for degradation.
March 15, 2018: Molecular Cell
https://www.readbyqxmd.com/read/29526694/ubiquitin-modulates-liquid-liquid-phase-separation-of-ubqln2-via-disruption-of-multivalent-interactions
#2
Thuy P Dao, Regina-Maria Kolaitis, Hong Joo Kim, Kevin O'Donovan, Brian Martyniak, Erica Colicino, Heidi Hehnly, J Paul Taylor, Carlos A Castañeda
Under stress, certain eukaryotic proteins and RNA assemble to form membraneless organelles known as stress granules. The most well-studied stress granule components are RNA-binding proteins that undergo liquid-liquid phase separation (LLPS) into protein-rich droplets mediated by intrinsically disordered low-complexity domains (LCDs). Here we show that stress granules include proteasomal shuttle factor UBQLN2, an LCD-containing protein structurally and functionally distinct from RNA-binding proteins. In vitro, UBQLN2 exhibits LLPS at physiological conditions...
March 15, 2018: Molecular Cell
https://www.readbyqxmd.com/read/29401586/polyq-expanded-huntingtin-and-ataxin-3-sequester-ubiquitin-adaptors-hhr23b-and-ubqln2-into-aggregates-via-conjugated-ubiquitin
#3
Hui Yang, Hong-Wei Yue, Wen-Tian He, Jun-Ye Hong, Lei-Lei Jiang, Hong-Yu Hu
The components of ubiquitin (Ub)-proteasome system, such as Ub, Ub adaptors, or proteasome subunits, are commonly accumulated with the aggregated proteins in inclusions, but how protein aggregates sequester Ub-related proteins remains elusive. Using N-terminal huntingtin (Htt-N552) and ataxin (Atx)-3 as model proteins, we investigated the molecular mechanism underlying sequestration of Ub adaptors by polyQ-expanded proteins. We found that polyQ-expanded Htt-N552 and Atx-3 sequester endogenous Ub adaptors, human RAD23 homolog B (hHR23B) and ubiquilin (UBQLN)-2, into inclusions...
January 11, 2018: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/29358706/the-mtm1-ubqln2-hsp-complex-mediates-degradation-of-misfolded-intermediate-filaments-in-skeletal-muscle
#4
Christos Gavriilidis, Leila Laredj, Romain Solinhac, Nadia Messaddeq, Julien Viaud, Jocelyn Laporte, Izabela Sumara, Karim Hnia
The ubiquitin proteasome system and autophagy are major protein turnover mechanisms in muscle cells, which ensure stemness and muscle fibre maintenance. Muscle cells contain a high proportion of cytoskeletal proteins, which are prone to misfolding and aggregation; pathological processes that are observed in several neuromuscular diseases called proteinopathies. Despite advances in deciphering the mechanisms underlying misfolding and aggregation, little is known about how muscle cells manage cytoskeletal degradation...
February 2018: Nature Cell Biology
https://www.readbyqxmd.com/read/29247619/a-new-drosophila-model-of-ubiquilin-knockdown-shows-the-effect-of-impaired-proteostasis-on-locomotive-and-learning-abilities
#5
Salinee Jantrapirom, Luca Lo Piccolo, Hideki Yoshida, Masamitsu Yamaguchi
Ubiquilin (UBQLN) plays a crucial role in cellular proteostasis through its involvement in the ubiquitin proteasome system and autophagy. Mutations in the UBQLN2 gene have been implicated in amyotrophic lateral sclerosis (ALS) and ALS with frontotemporal lobar dementia (ALS/FTLD). Previous studies reported a key role for UBQLN in Alzheimer's disease (AD); however, the mechanistic involvement of UBQLN in other neurodegenerative diseases remains unclear. The genome of Drosophila contains a single UBQLN homolog (dUbqn) that shows high similarity to UBQLN1 and UBQLN2; therefore, the fly is a useful model for characterizing the role of UBQLN in vivo in neurological disorders affecting locomotion and learning abilities...
January 15, 2018: Experimental Cell Research
https://www.readbyqxmd.com/read/29161404/mutation-dependent-aggregation-and-toxicity-in-a-drosophila-model-for-ubqln2-associated-als
#6
Sang Hwa Kim, Shannon G Stiles, Joseph M Feichtmeier, Nandini Ramesh, Lihong Zhan, Mark A Scalf, Lloyd M Smith, Udai Bhan Pandey, Randal S Tibbetts
Members of the conserved ubiquilin (UBQLN) family of ubiquitin (Ub) chaperones harbor an antipodal UBL (Ub-like)-UBA (Ub-associated) domain arrangement and participate in proteasome and autophagosome-mediated protein degradation. Mutations in a proline-rich-repeat region (PRR) of UBQLN2 cause amyotrophic lateral sclerosis (ALS)/frontotemporal dementia (FTD); however, neither the normal functions of the PRR nor impacts of ALS-associated mutations within it are well understood. In this study, we show that ALS mutations perturb UBQLN2 solubility and folding in a mutation-specific manner...
January 15, 2018: Human Molecular Genetics
https://www.readbyqxmd.com/read/29102476/investigating-ccnf-mutations-in-a-taiwanese-cohort-with-amyotrophic-lateral-sclerosis
#7
Pei-Chien Tsai, Yi-Chu Liao, Po-Lin Chen, Yuh-Cherng Guo, Ying-Hao Chen, Kang-Yang Jih, Kon-Ping Lin, Bing-Wen Soong, Ching-Paio Tsai, Yi-Chung Lee
Mutations in the cyclin F gene (CCNF) have been recently identified in a small number of patients with amyotrophic lateral sclerosis (ALS) and/or frontotemporal dementia, and their role in patients with ALS in Taiwan remains elusive. The aim of this study was to elucidate the frequency and spectrum of CCNF mutations in a Taiwanese ALS cohort of Han Chinese origin. Mutational analyses of the CCNF gene were performed using Sanger sequencing in a cohort of 255 unrelated patients with ALS. Among these patients, the genetic diagnoses of 204 patients remained unclear after mutations in SOD1, C9ORF72, TARDBP, FUS, ATXN2, OPTN, VCP, UBQLN2, SQSTM1, PFN1, HNRNPA1, HNRNPA2B1, MATR3, CHCHD10, TUBA4A, and TKB1 had been investigated...
February 2018: Neurobiology of Aging
https://www.readbyqxmd.com/read/28749476/the-wide-genetic-landscape-of-clinical-frontotemporal-dementia-systematic-combined-sequencing-of-121-consecutive-subjects
#8
Cornelis Blauwendraat, Carlo Wilke, Javier Simón-Sánchez, Iris E Jansen, Anika Reifschneider, Anja Capell, Christian Haass, Melissa Castillo-Lizardo, Saskia Biskup, Walter Maetzler, Patrizia Rizzu, Peter Heutink, Matthis Synofzik
PurposeTo define the genetic spectrum and relative gene frequencies underlying clinical frontotemporal dementia (FTD).MethodsWe investigated the frequencies and mutations in neurodegenerative disease genes in 121 consecutive FTD subjects using an unbiased, combined sequencing approach, complemented by cerebrospinal fluid Aβ1-42 and serum progranulin measurements. Subjects were screened for C9orf72 repeat expansions, GRN and MAPT mutations, and, if negative, mutations in other neurodegenerative disease genes, by whole-exome sequencing (WES) (n = 108), including WES-based copy-number variant (CNV) analysis...
February 2018: Genetics in Medicine: Official Journal of the American College of Medical Genetics
https://www.readbyqxmd.com/read/28716533/novel-ubqln2-mutations-linked-to-amyotrophic-lateral-sclerosis-and-atypical-hereditary-spastic-paraplegia-phenotype-through-defective-hsp70-mediated-proteolysis
#9
Elisa Teyssou, Laura Chartier, Maria-Del-Mar Amador, Roselina Lam, Géraldine Lautrette, Marie Nicol, Selma Machat, Sandra Da Barroca, Carine Moigneu, Mathilde Mairey, Thierry Larmonier, Safaa Saker, Christelle Dussert, Sylvie Forlani, Bertrand Fontaine, Danielle Seilhean, Delphine Bohl, Séverine Boillée, Vincent Meininger, Philippe Couratier, François Salachas, Giovanni Stevanin, Stéphanie Millecamps
Mutations in UBQLN2 have been associated with rare cases of X-linked juvenile and adult forms of amyotrophic lateral sclerosis (ALS) and ALS linked to frontotemporal dementia (FTD). Here, we report 1 known (c.1489C>T, p.Pro497Ser, P497S) and 3 novel (c.1481C>T, p.Pro494Leu, P494L; c.1498C>T, p.Pro500Ser, P500S; and c.1516C>G, p.Pro506Ala, P506A) missense mutations in the PXX domain of UBQLN2 in familial motor neuron diseases including ALS and spastic paraplegia (SP). A novel missense mutation (c...
October 2017: Neurobiology of Aging
https://www.readbyqxmd.com/read/28573364/-genetic-architecture-of-amyotrophic-lateral-sclerosis-and-frontotemporal-dementia-overlap-and-differences
#10
REVIEW
M Synofzik, M Otto, A Ludolph, J H Weishaupt
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) overlap not only clinically, but also with respect to shared neuropathology and genes. A large number of novel genes has recently been identified which underlie both diseases, e. g., C9orf72, TARDBP, GRN, TBK1, UBQLN2, VCP, CHCHD10, or SQSTM1. In contrast, other genes are still largely associated with only one of the two diseases, e. g., SOD1 with ALS or MAPT with FTD. These genetic findings indicate a large number of shared mechanisms, yet along with still a certain cell-specific vulnerability...
July 2017: Der Nervenarzt
https://www.readbyqxmd.com/read/28430856/a-comprehensive-analysis-of-rare-genetic-variation-in-amyotrophic-lateral-sclerosis-in-the-uk
#11
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...
June 1, 2017: Brain: a Journal of Neurology
https://www.readbyqxmd.com/read/28373810/a-turkish-family-with-a-familial-als-positive-ubqln2-s340i-mutation
#12
Dilcan Kotan, Ceren Iskender, Aslıhan Özoğuz Erimiş, A Nazlı Başak
No abstract text is available yet for this article.
September 2016: Noro Psikiyatri Arsivi
https://www.readbyqxmd.com/read/28315615/mir155-regulation-of-ubiquilin1-and-ubiquilin2-implications-in-cellular-protection-and-tumorigenesis
#13
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
https://www.readbyqxmd.com/read/28125704/no-evidence-for-pathogenic-role-of-ubqln2-mutations-in-sporadic-amyotrophic-lateral-sclerosis-in-the-mainland-chinese-population
#14
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
https://www.readbyqxmd.com/read/28105640/the-genotype-phenotype-landscape-of-familial-amyotrophic-lateral-sclerosis-in-australia
#15
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...
September 2017: Clinical Genetics
https://www.readbyqxmd.com/read/28103467/-investigation-of-genetic-etiology-in-neurodegenerative-dementias-recommendations-from-the-centro-hospitalar-s%C3%A3-o-jo%C3%A3-o-neurogenetics-group
#16
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
https://www.readbyqxmd.com/read/28057298/amyotrophic-lateral-sclerosis-pathogenesis-converges-on-defects-in-protein-homeostasis-associated-with-tdp-43-mislocalization-and-proteasome-mediated-degradation-overload
#17
REVIEW
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
https://www.readbyqxmd.com/read/27834214/motor-neuron-disease-tdp-43-pathology-and-memory-deficits-in-mice-expressing-als-ftd-linked-ubqln2-mutations
#18
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
#19
EDITORIAL
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
#20
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
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