Read by QxMD icon Read


Richard A Armstrong, Ann C McKee, Victor E Alvarez, Nigel J Cairns
Chronic traumatic encephalopathy (CTE) is a neurodegenerative disorder which may result from repetitive brain injury. A variety of tau-immunoreactive pathologies are present, including neurofibrillary tangles (NFT), neuropil threads (NT), dot-like grains (DLG), astrocytic tangles (AT), and occasional neuritic plaques (NP). In tauopathies, cellular inclusions in the cortex are clustered within specific laminae, the clusters being regularly distributed parallel to the pia mater. To determine whether a similar spatial pattern is present in CTE, clustering of the tau-immunoreactive pathology was studied in the cortex, hippocampus, and dentate gyrus in 11 cases of CTE and 7 cases of Alzheimer's disease neuropathologic change (ADNC) without CTE...
October 21, 2016: Journal of Neural Transmission
Cheng-Fu Chang, Yi-Chao Lee, Kuen-Haur Lee, Hui-Ching Lin, Chia-Ling Chen, Che-Kun James Shen, Chi-Chen Huang
BACKGROUND: In the central nervous system regions of the sporadic and familial FTLD and ALS patients, TDP-43 has been identified as the major component of UBIs inclusions which is abnormally hyperphosphorylated, ubiquitinated, and cleaved into C-terminal fragments to form detergent-insoluble aggregates. So far, the effective drugs for FTLD and ALS neurodegenerative diseases are yet to be developed. Autophagy has been demonstrated as the major metabolism route of the pathological TDP-43 inclusions, hence activation of autophagy is a potential therapeutic strategy for TDP-43 pathogenesis in FTLD and ALS...
October 21, 2016: Journal of Biomedical Science
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
Heiko Braak, Albert C Ludolph, Manuela Neumann, John Ravits, Kelly Del Tredici
Two nerve cells types, Betz cells in layer Vb of the primary motor neocortex and α-motoneurons of the lower brainstem and spinal cord, become involved at the beginning of the pathological cascade underlying sporadic amyotrophic lateral sclerosis (sALS). In both neuronal types, the cell nuclei forfeit their normal (non-phosphorylated) expression of the 43-kDa transactive response DNA-binding protein (TDP-43). Here, we present initial evidence that in α-motoneurons the loss of normal nuclear TDP-43 expression is followed by the formation of phosphorylated TDP-43 aggregates (pTDP-43) within the cytoplasm, whereas in Betz cells, by contrast, the loss of normal nuclear TDP-43 expression remains mostly unaccompanied by the development of cytoplasmic aggregations...
October 18, 2016: Acta Neuropathologica
A R Jayakumar, X Y Tong, N Shamaladevi, S Barcelona, G Gaidosh, A Agarwal, M D Norenberg
Transactivating DNA-binding protein-43 (TDP-43) inclusions and the accumulation of phosphorylated and ubiquitinated tau proteins (p-tau) have been identified in postmortem brain specimens from patients with chronic traumatic encephalopathy (CTE). To examine whether these proteins contribute to the development of CTE, we utilized an in vitro trauma system known to reproduce many of the findings observed in humans and experimental animals with traumatic brain injury. Accordingly, we examined the role of TDP-43 and Tau in an in vitro model of trauma, and determined whether these proteins contribute to the defective neuronal integrity associated with CNS trauma...
October 13, 2016: Journal of Neurochemistry
Atsushi Yamaguchi, Keisuke Takanashi
FUS (Fused-in-Sarcoma) is a multifunctional DNA/RNA binding protein linked to familial amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD). Since FUS is localized mainly in the nucleus with nucleo-cytoplasmic shuttling, it is critical to understand physiological functions in the nucleus to clarify pathogenesis. Here we report a yeast two-hybrid screening identified FUS interaction with nuclear matrix-associated protein SAFB1 (scaffold attachment factor B1). FUS and SAFB1, abundant in chromatin-bound fraction, interact in a DNA-dependent manner...
October 12, 2016: Scientific Reports
Angèle Nalbandian, Arif A Khan, Ruchi Srivastava, Katrina J Llewellyn, Baichang Tan, Nora Shukr, Yasmin Fazli, Virginia E Kimonis, Lbachir BenMohamed
Aberrant activation of the NOD-like receptor (NLR) family, pyrin domain-containing protein 3 (NLRP3) inflammasome, triggers a pathogenic inflammatory response in many inherited neurodegenerative disorders. Inflammation has recently been associated with valosin-containing protein (VCP)-associated diseases, caused by missense mutations in the VCP gene. This prompted us to investigate whether NLRP3 inflammasome plays a role in VCP-associated diseases, which classically affects the muscles, bones, and brain. In this report, we demonstrate (i) an elevated activation of the NLRP3 inflammasome in VCP myoblasts, derived from induced pluripotent stem cells (iPSCs) of VCP patients, which was significantly decreased following in vitro treatment with the MCC950, a potent and specific inhibitor of NLRP3 inflammasome; (ii) a significant increase in the expression of NLRP3, caspase 1, IL-1β, and IL-18 in the quadriceps muscles of VCP(R155H/+) heterozygote mice, an experimental mouse model that has many clinical features of human VCP-associated myopathy; (iii) a significant increase of number of IL-1β((+))F4/80((+))Ly6C((+)) inflammatory macrophages that infiltrate the muscles of VCP(R155H/+) mice; (iv) NLRP3 inflammasome activation and accumulation IL-1β((+))F4/80((+))Ly6C((+)) macrophages positively correlated with high expression of TDP-43 and p62/SQSTM1 markers of VCP pathology in damaged muscle; and (v) treatment of VCP(R155H/+) mice with MCC950 inhibitor suppressed activation of NLRP3 inflammasome, reduced the F4/80((+))Ly6C((+))IL-1β((+)) macrophage infiltrates in the muscle, and significantly ameliorated muscle strength...
October 11, 2016: Inflammation
Miguel Ángel Muñoz-Ruiz, Anette Hall, Jussi Mattila, Juha Koikkalainen, Sanna-Kaisa Herukka, Minna Husso, Tuomo Hänninen, Ritva Vanninen, Yawu Liu, Merja Hallikainen, Jyrki Lötjönen, Anne M Remes, Irina Alafuzoff, Hilkka Soininen, Päivi Hartikainen
BACKGROUND: Disease State Index (DSI) and its visualization, Disease State Fingerprint (DSF), form a computer-assisted clinical decision making tool that combines patient data and compares them with cases with known outcomes. AIMS: To investigate the ability of the DSI to diagnose frontotemporal dementia (FTD) and Alzheimer's disease (AD). METHODS: The study cohort consisted of 38 patients with FTD, 57 with AD and 22 controls. Autopsy verification of FTD with TDP-43 positive pathology was available for 14 and AD pathology for 12 cases...
May 2016: Dementia and Geriatric Cognitive Disorders Extra
Airi Tarutani, Shin-Ichi Hisanaga, Masato Hasegawa
Intracellular abnormal protein deposits, such as tau, α-synuclein and TDP-43, are the hallmark of many neurodegenerative diseases, and the distributions of these pathological proteins are closely correlated with disease symptoms and progression. A growing body of evidence strongly suggests that these abnormal proteins have prion-like properties: they convert normal proteins into abnormal forms, self-propagate through neuronal networks, and then spread in the brain. This prion-like propagation of abnormal proteins may account for the diversity, selective degeneration and disease progression seen in neurodegenerative diseases, although the molecular mechanism remains uncertain the molecular details of this mechanism...
October 2016: Brain and Nerve, Shinkei Kenkyū No Shinpo
Bryan D James, Robert S Wilson, Patricia A Boyle, John Q Trojanowski, David A Bennett, Julie A Schneider
Hyperphosphorylated transactive response DNA-binding protein 43 (TDP-43, encoded by TARDBP) proteinopathy has recently been described in ageing and in association with cognitive impairment, especially in the context of Alzheimer's disease pathology. To explore the role of mixed Alzheimer's disease and TDP-43 pathologies in clinical Alzheimer's-type dementia, we performed a comprehensive investigation of TDP-43, mixed pathologies, and clinical Alzheimer's-type dementia in a large cohort of community-dwelling older subjects...
September 30, 2016: Brain: a Journal of Neurology
Erika N Guerrero, Haibo Wang, Joy Mitra, Pavana M Hegde, Sara E Stowell, Nicole F Liachko, Brian C Kraemer, Ralph M Garruto, K S Rao, Muralidhar L Hegde
Amyotrophic lateral sclerosis (ALS), a common motor neuron disease affecting two per 100,000 people worldwide, encompasses at least five distinct pathological subtypes, including, ALS-SOD1, ALS-C9orf72, ALS-TDP-43, ALS-FUS and Guam-ALS. The etiology of a major subset of ALS involves toxicity of the TAR DNA-binding protein-43 (TDP-43). A second RNA/DNA binding protein, fused in sarcoma/translocated in liposarcoma (FUS/TLS) has been subsequently associated with about 1% of ALS patients. While mutations in TDP-43 and FUS have been linked to ALS, the key contributing molecular mechanism(s) leading to cell death are still unclear...
September 28, 2016: Progress in Neurobiology
Krista J Spiller, Clark R Restrepo, Tahiyana Khan, Anna M Stieber, Linda K Kwong, John Q Trojanowski, Virginia M-Y Lee
In order to treat progressive paralysis in ALS patients, it is critical to develop a mouse that closely models human ALS in both pathology and also in the timing of these events. We have recently generated new TDP-43 bigenic mice (called rNLS8) with doxycycline (Dox)-suppressible expression of human TDP-43 (hTDP-43) harboring a defective nuclear localization signal (hTDP-43∆NLS) under the control of the NEFH promoter. Our previous studies characterized the pathology and disease course in young rNLS8 mice following induction of neuronal hTDP-43ΔNLS...
September 29, 2016: Acta Neuropathologica Communications
Katerina Placek, Lauren Massimo, Christopher Olm, Kylie Ternes, Kim Firn, Vivianna Van Deerlin, Edward B Lee, John Q Trojanowski, Virginia M-Y Lee, David Irwin, Murray Grossman, Corey T McMillan
OBJECTIVE: To evaluate if cognitive reserve (CR) contributes to interindividual differences in frontal gray matter density (GMD) and executive impairment that underlie heterogeneity in the disease course of confirmed frontotemporal lobar degeneration (FTLD) pathology. METHODS: Fifty-five patients with autopsy confirmation or a pathogenic mutation consistent with underlying tau (FTLD-tau) or TDP-43 (FTLD-TDP) pathology and 90 demographically comparable healthy controls were assessed with T1 MRI and neuropsychological measures (Mini-Mental State Examination, letter fluency, forward digit span, Rey complex figure, and Boston Naming Test)...
September 28, 2016: Neurology
Jonathan P Ling, Resham Chhabra, Jonathan D Merran, Paul M Schaughency, Sarah J Wheelan, Jeffry L Corden, Philip C Wong
The fidelity of RNA splicing is maintained by a network of factors, but the molecular mechanisms that govern this process have yet to be fully elucidated. We previously found that TDP-43, an RNA-binding protein implicated in neurodegenerative disease, utilizes UG microsatellites to repress nonconserved cryptic exons and prevent their incorporation into mRNA. Here, we report that two well-characterized splicing factors, polypyrimidine tract-binding protein 1 (PTBP1) and polypyrimidine tract-binding protein 2 (PTBP2), are also nonconserved cryptic exon repressors...
September 27, 2016: Cell Reports
Yohei Iguchi, Lara Eid, Martin Parent, Geneviève Soucy, Christine Bareil, Yuichi Riku, Kaori Kawai, Shinnosuke Takagi, Mari Yoshida, Masahisa Katsuno, Gen Sobue, Jean-Pierre Julien
Cytoplasmic TDP-43 aggregation is a pathological hallmark of amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Here we investigated the role of exosomes in the secretion and propagation of TDP-43 aggregates. TDP-43 was detected in secreted exosomes from Neuro2a cells and primary neurons but not from astrocytes or microglia. Evidence is presented that protein aggregation and autophagy inhibition are factors that promote exosomal secretion of TDP-43. We also report that levels of exosomal TDP-43 full length and C-terminal fragment species are upregulated in human amyotrophic lateral sclerosis brains...
September 27, 2016: Brain: a Journal of Neurology
S Prpar Mihevc, Marco Baralle, Emanuele Buratti, Boris Rogelj
TDP-43 protein plays an important role in regulating transcriptional repression, RNA metabolism, and splicing. Typically it shuttles between the nucleus and the cytoplasm to perform its functions, while abnormal cytoplasmic aggregation of TDP-43 has been associated with neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). For the purpose of this study we selected a set of proteins that were misregulated following silencing of TDP-43 and analysed their expression in a TDP-43-aggregation model cell line HEK293 Flp-in Flag-TDP-43-12x-Q/N F4L...
September 26, 2016: Scientific Reports
Amanda Swain, Ziva Misulovin, Michelle Pherson, Maria Gause, Kathie Mihindukulasuriya, Ryan A Rickels, Ali Shilatifard, Dale Dorsett
The cohesin protein complex mediates sister chromatid cohesion and participates in transcriptional control of genes that regulate growth and development. Substantial reduction of cohesin activity alters transcription of many genes without disrupting chromosome segregation. Drosophila Nipped-B protein loads cohesin onto chromosomes, and together Nipped-B and cohesin occupy essentially all active transcriptional enhancers and a large fraction of active genes. It is unknown why some active genes bind high levels of cohesin and some do not...
September 2016: PLoS Genetics
H Bea Kuiperij, Alexandra A M Versleijen, Marijke Beenes, Nicolaas A Verwey, Luisa Benussi, Anna Paterlini, Giuliano Binetti, Charlotte E Teunissen, Joost Raaphorst, Helenius J Schelhaas, Benno Küsters, Yolande A L Pijnenburg, Roberta Ghidoni, Marcel M Verbeek
BACKGROUND: Frontotemporal dementia (FTD) is a heterogeneous disease both at the clinical, genetic, and pathobiological level. The underlying pathological spectrum (termed FTLD, frontotemporal lobar degeneration) is in most cases defined by accumulation of either tau (FTLD-tau) or TDP-43 proteins (FTLD-TDP). Biomarkers to differentiate these subtypes are not yet available, whereas these are essential requirements to study the natural course of disease and for homogeneous inclusion of patients in clinical studies...
September 23, 2016: Journal of Alzheimer's Disease: JAD
Stéphane Mathis, Philippe Couratier, Adrien Julian, Jean-Michel Vallat, Philippe Corcia, Gwendal Le Masson
INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a fatal progressive neurodegenerative disorder affecting both upper and lower motor neurons. Despite much research and effort, no clear insights into a unifying hypothesis for the pathogenesis has so far emerged for this disease. AREAS COVERED: We review the main pathophysiological hypotheses and the potential therapeutic targets in ALS, as well as the management of these patients (in order to improve their survival and quality of life)...
September 20, 2016: Expert Review of Neurotherapeutics
Koji Matsukawa, Tadafumi Hashimoto, Taisei Matsumoto, Ryoko Ihara, Takahiro Chihara, Masayuki Miura, Tomoko Wakabayashi, Takeshi Iwatsubo
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive and selective loss of motor neurons. Causative genes for familial ALS (fALS), e.g., TARDBP or FUS/TLS, have been found, among which mutations within the profilin 1 (PFN1) gene have recently been identified in ALS18. To elucidate the mechanism whereby PFN1 mutations lead to neuronal death, we generated transgenic Drosophila melanogaster overexpressing human PFN1 in the retinal photoreceptor neurons. Overexpression of wild-type or fALS mutant PFN1 caused no degenerative phenotypes in the retina...
September 15, 2016: Journal of Biological Chemistry
Fetch more papers »
Fetching more papers... Fetching...
Read by QxMD. Sign in or create an account to discover new knowledge that matter to you.
Remove bar
Read by QxMD icon Read

Search Tips

Use Boolean operators: AND/OR

diabetic AND foot
diabetes OR diabetic

Exclude a word using the 'minus' sign

Virchow -triad

Use Parentheses

water AND (cup OR glass)

Add an asterisk (*) at end of a word to include word stems

Neuro* will search for Neurology, Neuroscientist, Neurological, and so on

Use quotes to search for an exact phrase

"primary prevention of cancer"
(heart or cardiac or cardio*) AND arrest -"American Heart Association"