Tdp

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...

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...

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...

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...

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Thiamine is critical for cellular function, as its phosphorylated and active form, thiamine diphosphate (TDP), acts as coenzyme for three key enzymes in glucose metabolism. Mutations in thiamine transporter, TDP synthesizing enzyme or carrier, including solute carrier family 19 member 3 (SLC19A3), thiamine pyrophosphokinase (TPK1) and solute carrier family 25 member 19 (SLC25A19), have been associated with developmental neurological disorders, including microcephaly and Leigh syndrome. However, little is known about how thiamine metabolism regulates neuronal morphology at the cellular level...

BACKGROUND: With the growth of reverse shoulder arthroplasty (RSA), it is becoming increasingly necessary to establish the most cost-effective methods for the procedure. The surgical approach is one factor that may influence the cost and outcome of RSA. The purpose of this study was to compare the clinical results of a subscapularis- and deltoid-sparing (SSCS) approach to a traditional deltopectoral (TDP) approach for RSA. The hypothesis was that the SSCS approach would be associated with decreased length of stay (LOS), equal complication rate, and better short-term outcomes compared to the TDP approach...

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...

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...

Research on lake eutrophication often identifies variables affecting amounts of phosphorus (P) and nitrogen (N) in lakes, but understanding factors influencing N:P ratios is important given its influence on species composition and toxin production by cyanobacteria. We sampled 80 shallow lakes in Minnesota (USA) for three years to assess effects of watershed size, proportion of watershed as both row crop and natural area, fish biomass, and lake alternative state (turbid versus clear) on total N: total P (TN:TP), ammonium, total dissolved phosphorus (TDP), and seston stoichiometry...

STATEMENT OF PROBLEM: The manufacturers of computer-aided design and computer-aided manufacturing (CAD-CAM) systems emphasize that new technologies can improve the marginal fit of dental crowns. However, data supporting this claim are limited. PURPOSE: The purpose of this in vitro study was to investigate the differences among the following fabrication methods on the marginal discrepancy of dental crowns: intraoral optical scanners, powder application, and adjustments of intaglio surface...

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...

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...

Although millions of individuals suffer a traumatic brain injury (TBI) worldwide each year, it is only recently that TBI has been recognized as a major public health problem. Beyond the acute clinical manifestations, there is growing recognition that a single severe TBI (sTBI) or repeated mild TBIs (rTBI) can also induce insidious neurodegenerative processes, which may be associated with early dementia, in particular chronic traumatic encephalopathy (CTE). Identified at autopsy examination in individuals with histories of exposure to sTBI or rTBI, CTE is recognized as a complex pathology featuring both macroscopic and microscopic abnormalities...

Torsades de pointes (TdP)-an uncommon but life-threatening polymorphic ventricular tachycardia-is almost always drug induced. The authors describe the causes, risk factors, symptoms, diagnosis, and treatment of TdP.

Since its initial description by Jervell and Lange-Nielsen in 1957, the congenital long QT syndrome (LQTS) has been the most investigated cardiac ion channelopathy. A prolonged QT interval in the surface electrocardiogram is the sine qua non of the LQTS and is a surrogate measure of the ventricular action potential duration (APD). Congenital as well as acquired alterations in certain cardiac ion channels can affect their currents in such a way as to increase the APD and hence the QT interval. The inhomogeneous lengthening of the APD across the ventricular wall results in dispersion of APD...

AIM: We evaluated the diagnostic value of blood thiamine metabolites for Alzheimer's disease (AD) by using positron emission tomography with (11)C-Pittsburgh compound B ((11)C-PiB PET) scanning. METHODS: Thirty-eight clinically diagnosed AD patients were voluntarily recruited. Blood thiamine metabolites were measured by high-performance liquid chromatography. All the patients received (11)C-PiB PET scanning for the measurement of cerebral amyloid deposition. RESULTS: Thiamine diphosphate (TDP) had 66...

Microglia coordinate various functions in the central nervous system ranging from removing synaptic connections, to maintaining brain homeostasis by monitoring neuronal function, and clearing protein aggregates across the lifespan. Here we investigated whether increased microglial phagocytic activity that clears amyloid can also cause pathological synapse loss. We identified TDP-43, a DNA-RNA binding protein encoded by the Tardbp gene, as a strong regulator of microglial phagocytosis. Mice lacking TDP-43 in microglia exhibit reduced amyloid load in a model of Alzheimer's disease (AD) but at the same time display drastic synapse loss, even in the absence of amyloid...

Frontotemporal Lobar Degeneration (FTLD) encompasses certain related neurodegenerative disorders which alter personality and cognition. Heterogeneous ribonuclear proteins (hnRNPs) maintain RNA metabolism and changes in their function may underpin the pathogenesis of FTLD. Immunostaining for hnRNP E2 was performed on sections of frontal and temporal cortex with hippocampus from 80 patients with FTLD, stratified by pathology into FTLD-tau and FTLD-TDP type A, B and C subtypes, and by genetics into patients with C9orf72 expansions, MAPT or GRN mutations, or those with no known mutation, and on 10 healthy controls...

TDP-43 is a primarily nuclear RNA-binding protein, whose abnormal phosphorylation and cytoplasmic aggregation characterizes affected neurons in patients with amyotrophic lateral sclerosis and frontotemporal dementia. Here, we report that physiological nuclear TDP-43 in mouse and human brain forms homo-oligomers that are resistant to cellular stress. Physiological TDP-43 oligomerization is mediated by its N-terminal domain, which can adopt dynamic, solenoid-like structures, as revealed by a 2.1 Å crystal structure in combination with nuclear magnetic resonance spectroscopy and electron microscopy...