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https://www.readbyqxmd.com/read/28818672/glutathione-monoethyl-ester-prevents-tdp-43-pathology-in-motor-neuronal-nsc-34%C3%A2-cells
#1
Tong Chen, Bradley J Turner, Philip M Beart, Lucy Sheehan-Hennessy, Chinasom Elekwachi, Hakan Muyderman
Oxidative stress is recognised as central in a range of neurological diseases including Amyotrophic lateral sclerosis (ALS), a disease characterised by fast progressing death of motor neurons in the brain and spinal cord. Cellular pathology includes cytosolic protein aggregates in motor neurons and glia of which potentially cytotoxic hyper-phosphorylated fragments of the Transactive response DNA Binding Protein 43 kDa (TDP-43) constitute a major component. This is closely associated with an additional loss of nuclear TDP-43 expression indicating a "loss of function" mechanism, accelerating motor neuron (MN) loss...
August 14, 2017: Neurochemistry International
https://www.readbyqxmd.com/read/28817800/tia1-mutations-in-amyotrophic-lateral-sclerosis-and-frontotemporal-dementia-promote-phase-separation-and-alter-stress-granule-dynamics
#2
Ian R Mackenzie, Alexandra M Nicholson, Mohona Sarkar, James Messing, Maria D Purice, Cyril Pottier, Kavya Annu, Matt Baker, Ralph B Perkerson, Aishe Kurti, Billie J Matchett, Tanja Mittag, Jamshid Temirov, Ging-Yuek R Hsiung, Charles Krieger, Melissa E Murray, Masato Kato, John D Fryer, Leonard Petrucelli, Lorne Zinman, Sandra Weintraub, Marsel Mesulam, Julia Keith, Sasha A Zivkovic, Veronica Hirsch-Reinshagen, Raymond P Roos, Stephan Züchner, Neill R Graff-Radford, Ronald C Petersen, Richard J Caselli, Zbigniew K Wszolek, Elizabeth Finger, Carol Lippa, David Lacomis, Heather Stewart, Dennis W Dickson, Hong Joo Kim, Ekaterina Rogaeva, Eileen Bigio, Kevin B Boylan, J Paul Taylor, Rosa Rademakers
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are age-related neurodegenerative disorders with shared genetic etiologies and overlapping clinical and pathological features. Here we studied a novel ALS/FTD family and identified the P362L mutation in the low-complexity domain (LCD) of T cell-restricted intracellular antigen-1 (TIA1). Subsequent genetic association analyses showed an increased burden of TIA1 LCD mutations in ALS patients compared to controls (p = 8.7 × 10(-6)). Postmortem neuropathology of five TIA1 mutations carriers showed a consistent pathological signature with numerous round, hyaline, TAR DNA-binding protein 43 (TDP-43)-positive inclusions...
August 16, 2017: Neuron
https://www.readbyqxmd.com/read/28805003/protein-astrogliopathies-in-human-neurodegenerative-diseases-and-aging
#3
Gabor G Kovacs, Virginia M Lee, John Q Trojanowski
Neurodegenerative diseases are characterized by progressive dysfunction and loss of neurons associated with depositions of pathologically altered proteins showing hierarchical involvement of brain regions. The role of astrocytes in the pathogenesis of neurodegenerative diseases is explored as contributors to neuronal degeneration or neuroprotection pathways, and also as potential mediators of the transcellular spreading of disease-associated proteins. Protein astrogliopathy (PAG), including deposition of amyloid-β, prion protein, tau, α-synuclein, and very rarely transactive response DNA-binding protein 43 (TDP-43) is not unprecedented or unusual in neurodegenerative diseases...
September 2017: Brain Pathology
https://www.readbyqxmd.com/read/28804999/diversity-of-astroglial-responses-across-human-neurodegenerative-disorders-and-brain-aging
#4
Isidro Ferrer
Astrogliopathy refers to alterations of astrocytes occurring in diseases of the nervous system, and it implies the involvement of astrocytes as key elements in the pathogenesis and pathology of diseases and injuries of the central nervous system. Reactive astrocytosis refers to the response of astrocytes to different insults to the nervous system, whereas astrocytopathy indicates hypertrophy, atrophy/degeneration and loss of function and pathological remodeling occurring as a primary cause of a disease or as a factor contributing to the development and progression of a particular disease...
September 2017: Brain Pathology
https://www.readbyqxmd.com/read/28794432/tdp-43-stabilises-the-processing-intermediates-of-mitochondrial-transcripts
#5
Keiichi Izumikawa, Yuko Nobe, Harunori Yoshikawa, Hideaki Ishikawa, Yutaka Miura, Hiroshi Nakayama, Takashi Nonaka, Masato Hasegawa, Naohiro Egawa, Haruhisa Inoue, Kouki Nishikawa, Koji Yamano, Richard J Simpson, Masato Taoka, Yoshio Yamauchi, Toshiaki Isobe, Nobuhiro Takahashi
The 43-kDa trans-activating response region DNA-binding protein 43 (TDP-43) is a product of a causative gene for amyotrophic lateral sclerosis (ALS). Despite of accumulating evidence that mitochondrial dysfunction underlies the pathogenesis of TDP-43-related ALS, the roles of wild-type TDP-43 in mitochondria are unknown. Here, we show that the small TDP-43 population present in mitochondria binds directly to a subset of mitochondrial tRNAs and precursor RNA encoded in L-strand mtDNA. Upregulated expression of TDP-43 stabilised the processing intermediates of mitochondrial polycistronic transcripts and their products including the components of electron transport and 16S mt-rRNA, similar to the phenotype observed in cells deficient for mitochondrial RNase P...
August 9, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28793370/prevalence-of-tdp-43-proteinopathy-in-cognitively-normal-older-adults-systematic-review-and-meta-analysis
#6
Camila Nascimento, Ana Tereza Di Lorenzo Alho, Caroline Bazan Conceição Amaral, Renata Elane Paraizo Leite, Ricardo Nitrini, Wilson Jacob-Filho, Carlos Augusto Pasqualucci, Suvi Rosa Kastehelmi Hokkanen, Sally Hunter, Hannah Keage, Gabor G Kovacs, Lea Tenenholz Grinberg, Claudia Kimie Suemoto
OBJECTIVE: To perform a systematic review and meta-analysis on the prevalence of TDP-43 proteinopathy in cognitively normal older adults. METHODS: We systematically reviewed and performed a meta-analysis on the prevalence of TDP-43 proteinopathy in older adults with normal cognition, evaluated by the Mini-Mental State Examination or the Clinical Dementia Rating. We estimated the overall prevalence of TDP-43 using random-effect models, and stratified by age, sex, sample size, study quality, antibody used to assess TDP-43 aggregates, analyzed brain regions, Braak stage, CERAD score, hippocampal sclerosis, and geographic location...
August 9, 2017: Neuropathology and Applied Neurobiology
https://www.readbyqxmd.com/read/28793209/structural-rearrangement-upon-fragmentation-of-the-stability-core-of-the-als-linked-protein-tdp-43
#7
Brittany R Morgan, Jill A Zitzewitz, Francesca Massi
Amyotrophic lateral sclerosis (ALS) is the most common adult degenerative motor neuron disease. Experimental evidence indicates a direct role of transactive-response DNA-binding protein 43 (TDP-43) in the pathology of ALS and other neurodegenerative diseases. TDP-43 has been identified as a major component of cytoplasmic inclusions in patients with sporadic ALS; however, the molecular basis of the disease mechanism is not yet fully understood. Fragmentation within the second RNA recognition motif (RRM2) of TDP-43 has been observed in patient tissues and may play a role in the formation of aggregates in disease...
August 8, 2017: Biophysical Journal
https://www.readbyqxmd.com/read/28766957/immunohistochemical-detection-of-c9orf72-protein-in-frontotemporal-lobar-degeneration-and-motor-neurone-disease-patterns-of-immunostaining-and-an-evaluation-of-commercial-antibodies
#8
Yvonne S Davidson, Andrew C Robinson, Sara Rollinson, Stuart Pickering-Brown, Shangxi Xiao, Janice Robertson, David M A Mann
We have employed as 'gold standards' two in-house, well-characterised and validated polyclonal antibodies, C9-L and C9-S, which detect the longer and shorter forms of C9orf72, and have compared seven other commercially available antibodies with these in order to evaluate the utility of the latter as credible tools for the demonstration of C9orf72. C9-L and C9-S antibodies immunostained cytoplasmic 'speckles', and the nuclear membrane, respectively, in cerebellar Purkinje cells of the cerebellum in patients with behavioural variant frontotemporal dementia (bvFTD) with amyotrophic lateral sclerosis (ALS), and in patients with ALS alone...
August 2, 2017: Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration
https://www.readbyqxmd.com/read/28762175/genetic-mutations-in-rna-binding-proteins-and-their-roles-in-als
#9
REVIEW
Katannya Kapeli, Fernando J Martinez, Gene W Yeo
Mutations in genes that encode RNA-binding proteins (RBPs) have emerged as critical determinants of neurological diseases, especially motor neuron disorders such as amyotrophic lateral sclerosis (ALS). RBPs are involved in all aspects of RNA processing, controlling the life cycle of RNAs from synthesis to degradation. Hallmark features of RBPs in neuron dysfunction include misregulation of RNA processing, mislocalization of RBPs to the cytoplasm, and abnormal aggregation of RBPs. Much progress has been made in understanding how ALS-associated mutations in RBPs drive pathogenesis...
July 31, 2017: Human Genetics
https://www.readbyqxmd.com/read/28754988/zinc-binding-to-rna-recognition-motif-of-tdp-43-induces-the-formation-of-amyloid-like-aggregates
#10
Cyrille Garnier, François Devred, Deborah Byrne, Rémy Puppo, Andrei Yu Roman, Soazig Malesinski, Andrey V Golovin, Régine Lebrun, Natalia N Ninkina, Philipp O Tsvetkov
Aggregation of TDP-43 (transactive response DNA binding protein 43 kDa) is a hallmark of certain forms of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Moreover, intracellular TDP-43-positive inclusions are often found in other neurodegenerative diseases. Recently it was shown that zinc ions can provoke the aggregation of endogenous TDP-43 in cells, allowing to assume a direct interaction of TDP-43 with zinc ions. In this work, we investigated zinc binding to the 102-269 TDP-43 fragment, which comprise the two RNA recognition motifs...
July 28, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28733604/the-n-terminal-dimerization-is-required-for-tdp-43-splicing-activity
#11
Lei-Lei Jiang, Wei Xue, Jun-Ye Hong, Jun-Ting Zhang, Min-Jun Li, Shao-Ning Yu, Jian-Hua He, Hong-Yu Hu
TDP-43 is a nuclear factor that functions in promoting pre-mRNA splicing. Deletion of the N-terminal domain (NTD) and nuclear localization signal (NLS) (i.e., TDP-35) results in mislocalization to cytoplasm and formation of inclusions. However, how the NTD functions in TDP-43 activity and proteinopathy remains largely unknown. Here, we studied the structure and function of the NTD in inclusion formation and pre-mRNA splicing of TDP-43 by using biochemical and biophysical approaches. We found that TDP-43 NTD forms a homodimer in solution in a concentration-dependent manner, and formation of intermolecular disulfide results in further tetramerization...
July 21, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28724966/acetylation-induced-tdp-43-pathology-is-suppressed-by-an-hsf1-dependent-chaperone-program
#12
Ping Wang, Connor M Wander, Chao-Xing Yuan, Michael S Bereman, Todd J Cohen
TDP-43 pathology marks a spectrum of multisystem proteinopathies including amyotrophic lateral sclerosis, frontotemporal lobar degeneration, and sporadic inclusion body myositis. Surprisingly, it has been challenging to recapitulate this pathology, highlighting an incomplete understanding of TDP-43 regulatory mechanisms. Here we provide evidence supporting TDP-43 acetylation as a trigger for disease pathology. Using cultured cells and mouse skeletal muscle, we show that TDP-43 acetylation-mimics promote TDP-43 phosphorylation and ubiquitination, perturb mitochondria, and initiate degenerative inflammatory responses that resemble sporadic inclusion body myositis pathology...
July 19, 2017: Nature Communications
https://www.readbyqxmd.com/read/28719018/ante-mortem-csf-tau-levels-correlate-with-post-mortem-tau-pathology-in-ftld
#13
D J Irwin, A Lleó, S X Xie, C T McMillan, D Wolk, E B Lee, V M Van Deerlin, L M Shaw, J Q Trojanowski, M Grossman
OBJECTIVE: To test the hypotheses that 1) antemortem cerebrospinal fluid tau levels correlate with postmortem tau pathology in frontotemporal lobar degeneration and 2) tauopathy patients have higher phosphorylated-tau levels compared to TDP-43 proteinopathy patients while accounting for Alzheimer's disease co-pathology. METHODS: Patients had autopsy-confirmed frontotemporal lobar degeneration with tauopathy (n=31), TDP-43 proteinopathy (n=49), or Alzheimer's disease (n=26) with antemortem cerebrospinal fluid...
July 18, 2017: Annals of Neurology
https://www.readbyqxmd.com/read/28711596/the-relevance-of-contact-independent-cell-to-cell-transfer-of-tdp-43-and-sod1-in-amyotrophic-lateral-sclerosis
#14
REVIEW
Maya A Hanspal, Christopher M Dobson, Justin J Yerbury, Janet R Kumita
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease involving the formation of cytoplasmic aggregates by proteins including TDP-43 and SOD1, in affected cells in the central nervous system (CNS). Pathology spreads from an initial site of onset to contiguous anatomical regions. There is evidence that for disease-associated proteins, including TDP-43 and SOD1, non-native protein conformers can promote misfolding of the natively folded counterparts, and cell-to-cell transfer of pathological aggregates may underlie the spread of the disease throughout the CNS...
July 12, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28710326/cortical-influences-drive-amyotrophic-lateral-sclerosis
#15
REVIEW
Andrew Eisen, Heiko Braak, Kelly Del Tredici, Roger Lemon, Albert C Ludolph, Matthew C Kiernan
The early motor manifestations of sporadic amyotrophic lateral sclerosis (ALS), while rarely documented, reflect failure of adaptive complex motor skills. The development of these skills correlates with progressive evolution of a direct corticomotoneuronal system that is unique to primates and markedly enhanced in humans. The failure of this system in ALS may translate into the split hand presentation, gait disturbance, split leg syndrome and bulbar symptomatology related to vocalisation and breathing, and possibly diffuse fasciculation, characteristic of ALS...
July 14, 2017: Journal of Neurology, Neurosurgery, and Psychiatry
https://www.readbyqxmd.com/read/28708134/neurodegenerative-disease-loss-of-tdp-43-in-microglia-friend-or-foe
#16
Charlotte Ridler
No abstract text is available yet for this article.
August 2017: Nature Reviews. Neurology
https://www.readbyqxmd.com/read/28705014/mutation-in-the-rrm2-domain-of-tdp-43-in-amyotrophic-lateral-sclerosis-with-rapid-progression-associated-with-ubiquitin-positive-aggregates-in-cultured-motor-neurons
#17
Cindy Maurel, Blandine Madji-Hounoum, Rose-Anne Thepault, Sylviane Marouillat, Céline Brulard, Véronique Danel-Brunaud, Jean-Philippe Camdessanche, Helene Blasco, Philippe Corcia, Christian R Andres, Patrick Vourc'h
Mutations in the TAR-DNA Binding Protein-43 (TDP-43) encoding the TARDBP gene are present in amyotrophic lateral sclerosis (ALS). TDP-43 is the major component of ubiquitin-positive inclusions in motor neurons in ALS patients. We report here a novel heterozygous missense mutation in TARDBP in an ALS patient presenting a rapid form of ALS. This mutation p.N259S is located within the RNA recognition motif 2 (RRM2) in very close proximity with nucleotides in RNA. It is the first time a mutation was reported in this RRM2 domain of TDP-43...
July 13, 2017: Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration
https://www.readbyqxmd.com/read/28701108/repetitive-mild-closed-head-injury-alters-protein-expression-and-dendritic-complexity-in-a-mouse-model
#18
Jessica Nicole Saykally, Whitney A Ratliff, Kristen Keeley, Chaim G Pick, Ronald F Mervis, Bruce A Citron
World-wide head injuries are a growing problem. In the United States alone, 1.7 million people suffer a head injury each year. While most of these injuries are mild, head injury sufferers still sustain symptoms that can have major medical and economical impacts. Moreover, repetitive mild head injuries, like those observed in active military personnel and athletes, have demonstrated a more severe and long-term set of consequences. In an effort to better understand the delayed pathological changes following multiple mild head injuries, we used a mouse model of mild closed head injury (with no motor deficits observed by rotarod testing) and measured dendritic complexity at 30 days after injury and potentially related factors up to 60 days post injury...
July 12, 2017: Journal of Neurotrauma
https://www.readbyqxmd.com/read/28687523/tdp-43-in-the-spectrum-of-mnd-ftld-pathologies
#19
REVIEW
Lanier Heyburn, Charbel E-H Moussa
The relationship between RNA-binding proteins, particularly TAR DNA binding protein 43 (TDP-43), and neurodegeneration is an important area of research. TDP-43 is involved in so many cellular processes that perturbation of protein homeostasis can lead to countless downstream effects. Understanding what leads to this disease-related protein imbalance and the resulting cellular and molecular effects will help to develop targets for disease intervention, whether it be prevention of protein accumulation, or addressing a secondary effect of protein accumulation...
July 4, 2017: Molecular and Cellular Neurosciences
https://www.readbyqxmd.com/read/28686708/drosophila-lines-with-mutant-and-wild-type-human-tdp-43-replacing-the-endogenous-gene-reveals-phosphorylation-and-ubiquitination-in-mutant-lines-in-the-absence-of-viability-or-lifespan-defects
#20
Jer-Cherng Chang, David B Morton
Mutations in TDP-43 are associated with proteinaceous inclusions in neurons and are believed to be causative in neurodegenerative diseases such as frontotemporal dementia or amyotrophic lateral sclerosis. Here we describe a Drosophila system where we have engineered the genome to replace the endogenous TDP-43 orthologue with wild type or mutant human TDP-43(hTDP-43). In contrast to other models, these flies express both mutant and wild type hTDP-43 at similar levels to those of the endogenous gene and importantly, no age-related TDP-43 accumulation observed among all the transgenic fly lines...
2017: PloS One
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