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https://www.readbyqxmd.com/read/29777184/genotype-phenotype-links-in-frontotemporal-lobar-degeneration
#1
REVIEW
Sara Van Mossevelde, Sebastiaan Engelborghs, Julie van der Zee, Christine Van Broeckhoven
Frontotemporal lobar degeneration (FTLD) represents a group of neurodegenerative brain diseases with highly heterogeneous clinical, neuropathological and genetic characteristics. This high degree of heterogeneity results from the presence of several different underlying molecular disease processes; consequently, it is unlikely that all patients with FTLD will benefit from a single therapy. Therapeutic strategies for FTLD are currently being explored, and tools are urgently needed that enable the selection of patients who are the most likely to benefit from a particular therapy...
May 18, 2018: Nature Reviews. Neurology
https://www.readbyqxmd.com/read/29760195/neuron-specific-hur-deficient-mice-spontaneously-develop-motor-neuron-disease
#2
Kevin Sun, Xiao Li, Xing Chen, Ying Bai, Gao Zhou, Olga N Kokiko-Cochran, Bruce Lamb, Thomas A Hamilton, Ching-Yi Lin, Yu-Shang Lee, Tomasz Herjan
Human Ag R (HuR) is an RNA binding protein in the ELAVL protein family. To study the neuron-specific function of HuR, we generated inducible, neuron-specific HuR-deficient mice of both sexes. After tamoxifen-induced deletion of HuR, these mice developed a phenotype consisting of poor balance, decreased movement, and decreased strength. They performed significantly worse on the rotarod test compared with littermate control mice, indicating coordination deficiency. Using the grip-strength test, it was also determined that the forelimbs of neuron-specific HuR-deficient mice were much weaker than littermate control mice...
May 14, 2018: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/29581274/loss-of-tdp43-inhibits-progression-of-triple-negative-breast-cancer-in-coordination-with-srsf3
#3
Hao Ke, Limin Zhao, Honglei Zhang, Xu Feng, Haibo Xu, Junjun Hao, Shaowei Wang, Qin Yang, Li Zou, Xiaosan Su, Liqiong Wang, Chunlian Wu, Yang Wang, Jianyun Nie, Baowei Jiao
Aberrant alternative splicing has been highlighted as a potential hallmark of cancer. Here, we identify TDP43 (TAR DNA-binding protein 43) as an important splicing regulator responsible for the unique splicing profile in triple-negative breast cancer (TNBC). Clinical data demonstrate that TDP43 is highly expressed in TNBC with poor prognosis. Knockdown of TDP43 inhibits tumor progression, including proliferation and metastasis, and overexpression of TDP43 promotes proliferation and malignancy of mammary epithelial cells...
March 26, 2018: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29571878/expression-analysis-of-protein-homeostasis-pathways-in-the-peripheral-blood-mononuclear-cells-of-sporadic-amyotrophic-lateral-sclerosis-patients
#4
Abhishek Vats, Mandaville Gourie-Devi, Kavita Ahuja, Ankkita Sharma, Saima Wajid, Nirmal Kumar Ganguly, Vibha Taneja
Misfolded protein aggregates are the hallmark of Amyotrophic Lateral Sclerosis (ALS) which suggests involvement of protein homeostasis pathways in etiology of ALS. However, status of protein homeostasis in peripheral blood of ALS is not well established. We analyzed expression levels of key genes of proteostasis pathways in peripheral blood mononuclear cells (PBMCs) of sporadic ALS (sALS) patients and healthy controls. Increased protein carbonylation was observed in patients reflecting oxidative damage in PBMCs...
April 15, 2018: Journal of the Neurological Sciences
https://www.readbyqxmd.com/read/29545601/tdp43-nuclear-export-and-neurodegeneration-in-models-of-amyotrophic-lateral-sclerosis-and-frontotemporal-dementia
#5
Hilary C Archbold, Kasey L Jackson, Ayush Arora, Kaitlin Weskamp, Elizabeth M-H Tank, Xingli Li, Roberto Miguez, Robert D Dayton, Sharon Tamir, Ronald L Klein, Sami J Barmada
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are progressive neurodegenerative disorders marked in most cases by the nuclear exclusion and cytoplasmic deposition of the RNA binding protein TDP43. We previously demonstrated that ALS-associated mutant TDP43 accumulates within the cytoplasm, and that TDP43 mislocalization predicts neurodegeneration. Here, we sought to prevent neurodegeneration in ALS/FTD models using selective inhibitor of nuclear export (SINE) compounds that target exportin-1 (XPO1)...
March 15, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29499929/inhibition-of-tdp43-mediated-snhg12-mir-195-sox5-feedback-loop-impeded-malignant-biological-behaviors-of-glioma-cells
#6
Xiaobai Liu, Jian Zheng, Yixue Xue, Chengbin Qu, Jiajia Chen, Zhenhua Wang, Zhen Li, Lei Zhang, Yunhui Liu
Long non-coding RNA (lncRNA) dysregulation is involved in tumorigenesis and regulation of diverse cellular processes in gliomas. lncRNA SNHG12 is upregulated and promotes cell growth in human osteosarcoma cells. TAR-DNA binding protein 43 (TDP43) functions as an oncogene in various tumors by modulating RNA expression. Downregulation of TDP43 or SNHG12 significantly inhibited malignant biological behaviors of glioma cells. miR-195, downregulated in glioma tissues and cells, significantly impaired the malignant progression of glioma cells...
March 2, 2018: Molecular Therapy. Nucleic Acids
https://www.readbyqxmd.com/read/29472250/tau-protein-liquid-liquid-phase-separation-can-initiate-tau-aggregation
#7
Susanne Wegmann, Bahareh Eftekharzadeh, Katharina Tepper, Katarzyna M Zoltowska, Rachel E Bennett, Simon Dujardin, Pawel R Laskowski, Danny MacKenzie, Tarun Kamath, Caitlin Commins, Charles Vanderburg, Allyson D Roe, Zhanyun Fan, Amandine M Molliex, Amayra Hernandez-Vega, Daniel Muller, Anthony A Hyman, Eckhard Mandelkow, J Paul Taylor, Bradley T Hyman
The transition between soluble intrinsically disordered tau protein and aggregated tau in neurofibrillary tangles in Alzheimer's disease is unknown. Here, we propose that soluble tau species can undergo liquid-liquid phase separation (LLPS) under cellular conditions and that phase-separated tau droplets can serve as an intermediate toward tau aggregate formation. We demonstrate that phosphorylated or mutant aggregation prone recombinant tau undergoes LLPS, as does high molecular weight soluble phospho-tau isolated from human Alzheimer brain...
April 3, 2018: EMBO Journal
https://www.readbyqxmd.com/read/29439357/dale-schenk-one-year-anniversary-fighting-to-preserve-the-memories
#8
Cassia Overk, Eliezer Masliah
 It has been a year since we lost Dale Schenk on September 30, 2016. Dale's visionary work resulted in the remarkable discovery in 1999 that an experimental amyloid-β (Aβ) vaccine reduced the neurodegeneration in a transgenic model of Alzheimer's disease (AD). Following Dale's seminal work, several active and passive immunotherapies have since been developed and tested in the clinic for AD, Parkinson's disease (PD), and other neurodegenerative disorders. Here we provide a brief overview of the current state of development of immunotherapy for AD, PD, and other neurodegenerative disorders in the context of this anniversary...
2018: Journal of Alzheimer's Disease: JAD
https://www.readbyqxmd.com/read/29426953/cerebral-ischemia-induces-the-aggregation-of-proteins-linked-to-neurodegenerative-diseases
#9
Anja Kahl, Ismary Blanco, Katherine Jackman, Juhi Baskar, Harihar Milaganur Mohan, Reunet Rodney-Sandy, Sheng Zhang, Costantino Iadecola, Karin Hochrainer
Protein aggregation critically affects cell viability in neurodegenerative diseases, but whether this also occurs in ischemic brain injury remains elusive. Prior studies report the post-ischemic aggregation of ubiquitin, small ubiquitin-related modifier (SUMO) and ribosomes, however whether other proteins are also affected is unknown. Here we employed a proteomic approach to identify the insoluble, aggregated proteome after cerebral ischemia. Mice underwent transient middle cerebral artery occlusion or sham-surgery...
February 9, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29395044/tdp43-and-rna-instability-in-amyotrophic-lateral-sclerosis
#10
Kaitlin Weskamp, Sami J Barmada
The nuclear RNA-binding protein TDP43 is integrally involved in RNA processing. In accord with this central function, TDP43 levels are tightly regulated through a negative feedback loop, in which TDP43 recognizes its own RNA transcript, destabilizes it, and reduces new TDP43 protein production. In the neurodegenerative disorder amyotrophic lateral sclerosis (ALS), cytoplasmic mislocalization and accumulation of TDP43 disrupt autoregulation; conversely, inefficient TDP43 autoregulation can lead to cytoplasmic TDP43 deposition and subsequent neurodegeneration...
January 29, 2018: Brain Research
https://www.readbyqxmd.com/read/29382817/targeting-tyro3-ameliorates-a-model-of-pgrn-mutant-ftld-tdp-via-tau-mediated-synaptic-pathology
#11
Kyota Fujita, Xigui Chen, Hidenori Homma, Kazuhiko Tagawa, Mutsuki Amano, Ayumu Saito, Seiya Imoto, Hiroyasu Akatsu, Yoshio Hashizume, Kozo Kaibuchi, Satoru Miyano, Hitoshi Okazawa
Mutations in the progranulin (PGRN) gene cause a tau pathology-negative and TDP43 pathology-positive form of frontotemporal lobar degeneration (FTLD-TDP). We generated a knock-in mouse harboring the R504X mutation (PGRN-KI). Phosphoproteomic analysis of this model revealed activation of signaling pathways connecting PKC and MAPK to tau prior to TDP43 aggregation and cognitive impairments, and identified PKCα as the kinase responsible for the early-stage tau phosphorylation at Ser203. Disinhibition of Gas6 binding to Tyro3 due to PGRN reduction results in activation of PKCα via PLCγ, inducing tau phosphorylation at Ser203, mislocalization of tau to dendritic spines, and spine loss...
January 30, 2018: Nature Communications
https://www.readbyqxmd.com/read/29357796/autoimmunity-and-frontotemporal-dementia
#12
Antonella Alberici, Viviana Cristillo, Stefano Gazzina, Alberto Benussi, Alessandro Padovani, Barbara Borroni
Frontotemporal Dementia (FTD) is a neurodegenerative disorder which asymmetrically affects the frontotemporal lobes; it is characterized by behavioural abnormalities, language impairment, and deficits of executive functions. Behavioural variant FTD (bvFTD) and Primary Progressive Aphasias (PPAs) represent the most common phenotypes. The identification of mutations responsible for autosomal dominant inherited disorder, namely Microtubule Associated Protein Tau (MAPT), Granulin (GRN) and chromosome 9 open reading frame 72 (C9orf72) mutations, contributed to elucidate the molecular pathways involved in brain depositions of either Tau or TAR DNA-binding protein 43 (TDP43) inclusions...
January 18, 2018: Current Alzheimer Research
https://www.readbyqxmd.com/read/29215752/familial-tauopathy-with-p364s-mapt-mutation-clinical-course-neuropathology-and-ultrastructure-of-neuronal-tau-inclusions
#13
P Štrafela, J Pleško, J Magdič, B Koritnik, A Zupan, D Glavač, M Bresjanac, M Popović
AIMS: This report presents the clinical course, neuropathology and ultrastructure of neuronal tau inclusions of four Slovene relatives with P364S MAPT mutation. METHODS: The clinical history of three out of four P364S MAPT mutation carriers was taken. After formalin fixation, thorough sampling of the central nervous system was followed by paraffin embedding, H&E, Gallyas, Bielschowsky and immunostaining with AT8, anti-3R, anti-4R tau, anti-amyloid-β, anti-TDP43 and anti-alpha-synuclein antibodies...
December 7, 2017: Neuropathology and Applied Neurobiology
https://www.readbyqxmd.com/read/29097599/brains-with-sporadic-creutzfeldt-jakob-disease-and-copathology-showed-a-prolonged-end-stage-of-disease
#14
Aitzol Miguelez-Rodriguez, Jorge Santos-Juanes, Ikerne Vicente-Etxenausia, Katty Perez de Heredia-Goñi, Beatriz Garcia, Luis M Quiros, Laura Lorente-Gea, Isabel Guerra-Merino, Jose J Aguirre, Ivan Fernandez-Vega
AIMS: To investigate the expression of major proteins related to primary neurodegenerative diseases and their prognostic significance in brains with Creutzfeldt-Jakob disease (CJD). MATERIALS AND METHODS: Thirty consecutive cases of confirmed CJD during the period 2010-2015 at Basque Brain bank were retrospectively reviewed. Moreover, major neurodegenerative-associated proteins (phosphorylated Tau, 4R tau, 3R tau, alpha-synuclein, TDP43, amyloid beta) were tested...
November 2, 2017: Journal of Clinical Pathology
https://www.readbyqxmd.com/read/28894122/onset-of-disorder-and-protein-aggregation-due-to-oxidation-induced-intermolecular-disulfide-bonds-case-study-of-rrm2-domain-from-tdp-43
#15
Sevastyan O Rabdano, Sergei A Izmailov, Dmitrii A Luzik, Adam Groves, Ivan S Podkorytov, Nikolai R Skrynnikov
We have investigated the behavior of second RNA-recognition motif (RRM2) of neuropathological protein TDP43 under the effect of oxidative stress as modeled in vitro. Toward this end we have used the specially adapted version of H/D exchange experiment, NMR relaxation and diffusion measurements, dynamic light scattering, controlled proteolysis, gel electrophoresis, site-directed mutagenesis and microsecond MD simulations. Under oxidizing conditions RRM2 forms disulfide-bonded dimers that experience unfolding and then assemble into aggregate particles (APs)...
September 11, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28751743/anti-ampa-glua3-antibodies-in-frontotemporal-dementia-a-new-molecular-target
#16
B Borroni, J Stanic, C Verpelli, M Mellone, E Bonomi, A Alberici, P Bernasconi, L Culotta, E Zianni, S Archetti, M Manes, S Gazzina, R Ghidoni, L Benussi, C Stuani, M Di Luca, C Sala, E Buratti, A Padovani, F Gardoni
Frontotemporal Dementia (FTD) is a neurodegenerative disorder mainly characterised by Tau or TDP43 inclusions. A co-autoimmune aetiology has been hypothesised. In this study, we aimed at defining the pathogenetic role of anti-AMPA GluA3 antibodies in FTD. Serum and cerebrospinal fluid (CSF) anti-GluA3 antibody dosage was carried out and the effect of CSF with and without anti-GluA3 antibodies was tested in rat hippocampal neuronal primary cultures and in differentiated neurons from human induced pluripotent stem cells (hiPSCs)...
July 27, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28632899/novel-intracytoplasmic-inclusions-immunoreactive-for-phosphorylated-tdp43-and-cystatin-c-in-anterior-horn-cells-in-a-case-of-sporadic-amyotrophic-lateral-sclerosis
#17
Masayuki Shintaku, Daita Kaneda, Kiyomitsu Oyanagi
Novel intracytoplasmic inclusions immunoreactive for phosphorylated transactivation response DNA-binding protein 43 (p-TDP43), cystatin C, and transferrin were found in anterior horn cells in a case of sporadic amyotrophic lateral sclerosis (ALS). The patient was a 59-year-old woman, who died of ALS after a clinical course of 8 years. She had been receiving mechanical support for respiration for 6 years and in a "totally locked-in" state for 4 years prior to death. The spinal cord showed severe degeneration involving the anterior and lateral funiculi, whereas the posterior funiculus was preserved...
December 2017: Neuropathology: Official Journal of the Japanese Society of Neuropathology
https://www.readbyqxmd.com/read/28582864/transactive-dna-binding-protein-43-rather-than-other-misfolded-proteins-in-the-brain-is-associated-with-islet-amyloid-polypeptide-in-pancreas-in-aged-subjects-with-diabetes-mellitus
#18
Marina Leino, Svetlana N Popova, Irina Alafuzoff
A link between diabetes mellitus (DM) related islet amyloid polypeptide (IAPP) and Alzheimer's disease (AD) related amyloid-β (Aβ) has been suggested in epidemiological and clinical studies. In 2017, proof for existing interaction between type 2 DM and AD on a molecular level was provided based on research carried out in experimental animal models. We assessed aging-related neurodegenerative lesions, i.e., misfolded proteins, associated with dementia such as hyperphosphorylated τ (HPτ), Aβ, α-synuclein (αS), and phosphorylated transactive DNA binding protein 43 (pTDP43) seen in the brain and IAPP seen in the pancreas in subjects with and without DM applying immunohistochemical techniques...
2017: Journal of Alzheimer's Disease: JAD
https://www.readbyqxmd.com/read/28521037/clinical-significance-of-tdp-43-neuropathology-in-amyotrophic-lateral-sclerosis
#19
Matthew D Cykowski, Suzanne Z Powell, Leif E Peterson, Joan W Appel, Andreana L Rivera, Hidehiro Takei, Ellen Chang, Stanley H Appel
To determine the significance of TAR DNA binding protein 43 kDa (TDP-43) pathology in amyotrophic lateral sclerosis (ALS), we examined the whole brains and spinal cords of 57 patients (35 men; 22 women; mean age 63.3 years; 15 patients with c9orf72-associated ALS [c9ALS]). TDP-43 pathologic burden was determined relative to symptom onset site, disease duration, progression rate, cognitive status, and c9ALS status. There was a trend for greater TDP-43 pathologic burden in cognitively impaired patients (p = 0...
May 1, 2017: Journal of Neuropathology and Experimental Neurology
https://www.readbyqxmd.com/read/28330421/the-proteinopathy-of-d169g-and-k263e-mutants-at-the-rna-recognition-motif-rrm-domain-of-tar-dna-binding-protein-tdp43-causing-neurological-disorders-a-computational-study
#20
Vishwambhar Vishnu Bhandare, Amutha Ramaswamy
One of the multitasking proteins, transactive response DNA-binding protein 43 (tdp43) plays a key role in RNA regulation and the two pathogenic mutations such as D169G and K263E, located at the RNA Recognition Motif (RRM) of tdp43, are reported to cause neurological disorders such as Amyotrophic Lateral Sclerosis and FrontoTemporal Lobar Degeneration. As the exploration of the proteinopathy demands both structural and functional characterizations of mutants, a comparative analysis on the wild type and mutant tdp43 (D169G and K263E) and their complexes with RNA has been performed using computational approaches...
March 2018: Journal of Biomolecular Structure & Dynamics
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