OBJECTIVE: To assess the transactive response DNA-binding protein 43 (TDP-43) burden in familial forms of Alzheimer disease (FAD) and Down syndrome (DS) to determine whether TDP-43 inclusions are also present. DESIGN: Using standard immunohistochemical techniques, we examined brain tissue samples from 42 subjects with FAD and 14 with DS. RESULTS: We found pathological TDP-43 aggregates in 14.0% of participants (6 of 42 and 2 of 14 participants with FAD and DS, respectively). In both FAD and DS, TDP-43 immunoreactivity did not colocalize with neurofibrillary tangles. Occasionally participants with FAD or DS had TDP-43-positive neuropil threads or dots. Overall, the amygdala was most commonly affected, followed by the hippocampus, with no TDP-43 pathology in neocortical regions. A similar distribution of TDP-43 inclusions is seen in sporadic Alzheimer disease, but it differs from that seen in amyotrophic lateral sclerosis and frontotemporal dementia. CONCLUSIONS: Transactive response DNA-binding ...
The co-existence of multiple pathologies and proteins is a common feature in the brains of cognitively impaired elderly individuals. Transactive response DNA-binding protein (TDP-43) has been discovered to accumulate in limbic brain regions of a portion of late-onset Alzheimers disease (AD) patients, in addition to amyloid-β and τ protein. However, it is not yet known whether the TDP-43 species in the AD brain differ in their composition, when compared among different AD cases and to frontotemporal lobar degeneration cases with TDP-43 inclusions (FTLD-TDP). Furthermore, it is not known whether TDP-43 pathology in AD is related to symptoms of the frontotemporal dementia (FTD) spectrum. In this study, we investigated the molecular pattern of TDP-43 lesions with five different antibodies against different phosphorylated (pTDP-43) and non-phosphorylated TDP-43 epitopes. We analyzed a cohort of 97 autopsy cases, including brains from 20 non-demented individuals, 16 cognitively normal pathologically
Humans carry an RNA-processing protein called the transactive response DNA-binding protein, or TARDBP/TDP-43. The protein has been linked to a number of neurodegenerative disorders that involve protein misfolding, such as amyotrophic lateral sclerosis and frontotemporal lobar degeneration. In a recent Paper of the Week published in the Journal of Biological Chemistry, Jiou Wang at The Johns Hopkins University and colleagues described a Caenorhabditis elegans model in which they removed the worm version of the TDP-43 protein, called TDP-1 (1).. Why the worm? Although mammals such as mice offer important models for human diseases, sometimes the complexity of the mammalian systems prevent the unraveling of basic functions of a molecule, explains Wang. For example, the TDP-43 knockout mice die in early embryogenesis, making it difficult to tease out the physiological functions of the protein.. Wangs team showed that the worm and human versions of the RNA-processing protein were very similar. ...
Amyotrophic lateral sclerosis (ALS) is a relentlessly progressive neurodegenerative disorder, and cytoplasmic inclusions containing transactive response (TAR) DNA binding protein (TDP-43) are present in ~90 % of cases. Here we report detailed pathology in human TDP-43 transgenic mice that recapitulate key features of TDP-43-linked ALS. Expression of human wild-type TDP-43 (TDP-43WT) caused no clinical or pathological phenotype, while expression of Q331K mutant (TDP-43Q331K) resulted in a non-lethal age-dependent motor phenotype, accompanied by cytoplasmic TDP-43 aggregation, mild neuronal loss, with astroglial and microglial activation in the motor cortex and spinal cord at 24 months. However, co-expression of WT and Q331K mutant (TDP-43WTxQ331K) resulted in an extremely aggressive motor phenotype with tremor from 3 weeks and progressive hind-limb paralysis necessitating euthanasia by 8-10 weeks of age. Neuronal loss and reactive gliosis was observed in the spinal cord and layer V region of the cortex,
TY - JOUR. T1 - HDAC1 dysregulation induces aberrant cell cycle and DNA damage in progress of TDP-43 proteinopathies. AU - Wu, Cheng Chun. AU - Jin, Lee Way. AU - Wang, I. Fang. AU - Wei, Wei Yen. AU - Ho, Pei Chuan. AU - Liu, Yu Chih. AU - Tsai, Kuen Jer. N1 - Funding Information: The authors are grateful to University of California Davis Alzheimers Disease Center, funded by National Institute on Aging (NIA, grant #P30AG10129) for collecting and providing the human samples. This study was performed, in part, with support from Taiwan Ministry of Science and Technology (NSC‐102‐2320‐B‐006‐040‐MY3, MOST‐103‐2321‐B‐006‐028, MOST‐104‐2321‐B‐006‐010, MOST‐105‐2321‐B‐006‐ 002, MOST‐105‐2628‐B‐006‐016‐MY3, and MOST‐106‐2628‐B‐006‐001‐MY4). PY - 2020/6/8. Y1 - 2020/6/8. N2 - TAR DNA-binding protein 43 (TDP-43) has been implicated in frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-TDP) and amyotrophic lateral ...
TY - JOUR. T1 - Coaggregation of RNA-binding proteins in a model of TDP-43 proteinopathy with selective RGG motif methylation and a role for RRM1 ubiquitination. AU - Dammer, Eric B.. AU - Fallini, Claudia. AU - Gozal, Yair M.. AU - Duong, Duc M.. AU - Rossoll, Wilfried. AU - Xu, Ping. AU - Lah, James J.. AU - Levey, Allan I.. AU - Peng, Junmin. AU - Bassell, Gary J.. AU - Seyfried, Nicholas T.. PY - 2012/6/21. Y1 - 2012/6/21. N2 - TAR DNA-binding protein 43 (TDP-43) is a major component within ubiquitin-positive inclusions of a number of neurodegenerative diseases that increasingly are considered as TDP-43 proteinopathies. Identities of other inclusion proteins associated with TDP-43 aggregation remain poorly defined. In this study, we identify and quantitate 35 co-aggregating proteins in the detergent-resistant fraction of HEK-293 cells in which TDP-43 or a particularly aggregate prone variant, TDP-S6, were enriched following overexpression, using stable isotope-labeled (SILAC) internal ...
Mitochondrial dysfunction has been linked to the pathogenesis of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Functional studies of mitochondrial bioenergetics have focused mostly on superoxide dismutase 1 (SOD1) mutants, and showed that mutant human SOD1 impairs mitochondrial oxidative phosphorylation, calcium homeostasis, and dynamics. However, recent reports have indicated that alterations in transactivation response element DNA-binding protein 43 (TDP-43) can also lead to defects of mitochondrial morphology and dynamics. Furthermore, it was proposed that TDP-43 mutations cause oxidative phosphorylation impairment associated with respiratory chain defects and that these effects were caused by mitochondrial localization of the mutant protein. Here, we investigated the presence of bioenergetic defects in the brain of transgenic mice expressing human mutant TDP-43 (TDP-43A315T mice), patient derived fibroblasts, and human cells expressing mutant forms of TDP-43. In
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Recent studies in neurodegenerative conditions have increasingly highlighted that the same neuropathology can trigger different clinical phenotypes or, vice-versa, that similar phenotypes can be triggered by different neuropathologies. This evidence has called for the adoption of a pathology spectrum-based approach to study neurodegenerative proteinopathies. These conditions share brain deposition of abnormal protein aggregates, leading to aberrant biochemical, metabolic, functional, and structural changes. Positron emission tomography (PET) is a well-recognized and unique tool for the in vivo assessment of brain neuropathology, and novel PET techniques are emerging for the study of specific protein species. Today, key applications of PET range from early research and clinical diagnostic tools to their use in clinical trials for both participants screening and outcome evaluation. This position article critically reviews the role of distinct PET molecular tracers for different neurodegenerative ...
The identification of TDP-43 as the major component of the pathologic inclusions in most forms of sporadic and familial frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U) and amyotrophic lateral sclerosis (ALS) resolved a long-standing enigma concerning the nature of the ubiquitinated disease protein under these conditions. Anti-TDP-43 immunohistochemistry and the recent development of novel tools, such as phosphorylation-specific TDP-43 antibodies, have increased our knowledge about the spectrum of pathological changes associated with FTLD-U and ALS and moreover, facilitated the neuropathological routine diagnosis of these conditions. This review summarizes the recent advances in our understanding on the molecular neuropathology and pathobiology of TDP-43 in FTLD and ALS.
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The physiological AKT-MTORC1 and AMPK signaling pathways are considered key nodes in the regulation of anabolism-catabolism, and particularly of macroautophagy/autophagy. Indeed, it is reported that these are altered processes in neurodegenerative proteinopathies such as Alzheimer disease (AD), mainly characterized by deposits of β-amyloid (Aβ) and hyperphosphorylated MAPT. These accumulations disrupt the optimal neuronal proteostasis, and hence, the recovery/enhancement of autophagy has been proposed as a therapeutic approach against these proteinopathies. The purpose of the present study was to characterize the modulation of autophagy by MTORC1 and AMPK signaling pathways in the highly specialized neurons, as well as their repercussions on Aβ production. Using a double transgenic mice model of AD, we demonstrated that MTORC1 inhibition, either in vivo or ex vivo (primary neuronal cultures), was able to reduce amyloid secretion through moderate autophagy induction in neurons. The ...
The normally soluble TAR DNA-binding protein 43 (TDP-43) is found aggregated both in reversible stress granules and in irreversible pathogenic amyloid. In TDP-43, the low-complexity domain (LCD) is believed to be involved in both types of aggregation. To uncover the structural origins of these two modes of β-sheet-rich aggregation, we have determined ten structures of segments of the LCD of human TDP-43. Six of these segments form steric zippers characteristic of the spines of pathogenic amyloid fibrils; four others form LARKS, the labile amyloid-like interactions characteristic of protein hydrogels and proteins found in membraneless organelles, including stress granules. Supporting a hypothetical pathway from reversible to irreversible amyloid aggregation, we found that familial ALS variants of TDP-43 convert LARKS to irreversible aggregates. Our structures suggest how TDP-43 adopts both reversible and irreversible β-sheet aggregates and the role of mutation in the possible transition of ...
Transactive memory theory views communication as a valuable (but not perfect) tool for learning, storing, and retrieving information from other people. In this
TMEM106B has a strong association with brain pathology and was discovered as a risk allele in diseases on the ALS/FTLD spectrum. But indeed, the main impact of TDP-43 proteinopathy on public health is on LATE, which is ,100-fold more common than ALS/FTLD conditions (~1:3 lifetime risk versus ,1:1000 lifetime risk). Its interesting that the rare variant of TMEM106B is actually protective.. This new contribution by Yang and colleagues and the Rush University group is significant, and focused on LATE. This paper shows evidence of pathways that both TMEM106B and APOE contribute to, and there has been published evidence (including from Rush) that both TMEM106B and APOE status are associated with risk for TDP-43 proteinopathy in advanced age. One question that I had was whether or not other pathways associated with LATE show signals. GRN is only mentioned somewhat tangentially, whereas ABCC9 and KCNMB2 are not discussed.. ...
William T. Hu and Murray Grossman Current Neurology and Neuroscience Reports 9:353-358, 2009 Abstract TAR DNA-binding protein of about 43 kDa (TDP-43) is the main ubiquitinated peptide in tau-negative frontotemporal lobar ...
Respiration Enhances TDP-43 Toxicity, but TDP-43 Retains Some Toxicity in the Absence of Respiration. Park SK, Park S, Liebman SW. J Mol Biol. 2019 May 3;431(10):2050-2059. doi: 10.1016/j.jmb.2019.03.014. Epub 2019 Mar 21. ...
TAR DNA-binding protein 43 (TDP-43) is the disease protein in frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U) and Bosutinib amyotrophic lateral sclerosis (ALS). normal nuclear TDP-43 whereas TDP-43-ΔNES forms insoluble nuclear aggregates with endogenous TDP-43. Mutant forms of TDP-43 also replicate the biochemical profile of pathological TDP-43 in FTLD-U/ALS. Thus FTLD-U/ALS pathogenesis may be linked mechanistically to deleterious perturbations of nuclear trafficking and solubility of TDP-43. TAR DNA-binding protein 43 (TDP-43) encoded by the gene on chromosome 1 is a highly conserved ubiquitously expressed nuclear protein implicated in repression of gene transcription inhibition of exon splicing and interactions with splicing factors and nuclear bodies (1 2 Recently we identified TDP-43 as the disease protein forming insoluble aggregates in the central nervous system of patients with frontotemporal lobar degeneration (FTLD)2 and amyotrophic lateral sclerosis ...
TY - JOUR. T1 - Distribution and characteristics of transactive response DNA binding protein 43 kDa pathology in progressive supranuclear palsy. AU - Koga, Shunsuke. AU - Sanchez-Contreras, Monica. AU - Josephs, Keith Anthony. AU - Uitti, Ryan J.. AU - Graff Radford, Neill R. AU - Van Gerpen, Jay A. AU - Cheshire, William P.. AU - Wszolek, Zbigniew K. AU - Rademakers, Rosa V. AU - Dickson, Dennis W. PY - 2016. Y1 - 2016. N2 - Background: This study aimed to determine the frequency of transactive response DNA binding protein 43 kDa pathology in PSP, the clinical features of patients with this pathology, and genetic risk factors for it. Methods: Hippocampal sections were screened with immunohistochemistry for transactive response DNA binding protein 43 kDa in 945 PSP cases. A subset of 261 cases that were negative in hippocampus was screened in the amygdala. The density and disruption of this pathology, as well as regional tau burden, and clinical and genetic characteristics were analyzed. ...
The transactive response DNA-binding protein 43 (TDP-43) has been identified as a neurofilament light (NF-L) messenger RNA (mRNA)-binding protein. Abnormally increased levels of TDP-43 are detected in patients with amyotrophic lateral sclerosis and a downregulation of NF-L mRNA. However, links between NF-L and TDP-43 expressions are unclear. In this study, we investigated whether the deficiency of NF-L protein can result in alterations in TDP-43 localization or protein expression and whether this is altered with aging. There was a significant increase in TDP-43 protein levels in the cortex and lumbar spinal cord in 12-month-old NF-L knockout (NF-L KO) mice, compared with wild-type (WT) C57BL/6 mice. However, there was no difference in either the phosphorylation of TDP-43 between WT and NF-L KO mice or the abnormal mislocalization of TDP-43 to the cytoplasm in NF-L KO animals. Our findings suggest that NF-L protein or mRNA may negatively affect the expression of TDP-43 in the central nervous ...
Valosin-containing protein (VCP) is involved in multiple cellular activities. Mutations in VCP lead to heterogeneous clinical presentations including inclusion body myopathy with Pagets disease of the bone, frontotemporal dementia and amyotrophic lateral sclerosis, even in patients carrying the same mutation. We screened a cohort of 48 patients with familial frontotemporal dementia (FTD) negative for MAPT, GRN, and C9orf72 mutations for other known FTD genes by using whole exome sequencing. In addition, we carried out targeted sequencing of a cohort of 37 patients with frontotemporal lobar degeneration with Transactive response DNA-binding protein 43 (TDP-43) subtype from the Netherlands Brain bank. Two novel (p.Thr262Ser and p.Arg159Ser) and one reported (p.Met158Val) VCP mutations in three patients with a clinical diagnosis of FTD were identified, and were absence in population-match controls. All three patients presented with behavioral changes, with additional semantic deficits in one. No ...
TAR DNA-binding protein 43 (TDP-43; see Drosophila TDP-43) is a major disease protein in amyotrophic lateral sclerosis (ALS) and related neurodegenerative diseases. Both the cytoplasmic accumulation of toxic ubiquitinated and hyperphosphorylated TDP-43 fragments and the loss of normal TDP-43 from the nucleus may contribute to the disease progression by impairing normal RNA and protein homeostasis. Therefore, both the removal of pathological protein and the rescue of TDP-43 mislocalization may be critical for halting or reversing TDP-43 proteinopathies. This study reports poly(A)-binding protein nuclear 1 (PABPN1) as a novel TDP-43 interaction partner that acts as a potent suppressor of TDP-43 toxicity. Overexpression of full-length PABPN1 but not a truncated version lacking the nuclear localization signal protects from pathogenic TDP-43-mediated toxicity, promotes the degradation of pathological TDP-43 and restores normal solubility and nuclear localization of endogenous TDP-43. Reduced levels ...
The abnormal accumulation of phosphorylated and ubiquitinated species in protein inclusions is observed in a wide variety of neurodegenerative diseases (3, 4). In Alzheimer and Parkinson diseases, these intracellular inclusions are called neurofibrillary tangles and Lewy bodies and are composed of pathologically altered forms of tau and α-synuclein, respectively (3, 52). In FTLD-U and ALS, TDP-43 has been identified as the major component of tau- and α-synuclein-negative inclusions where it is both phosphorylated and ubiquitinated (5). Although there are 10 known splice variants of human TDP-43, their roles in abnormal TDP-43 translocation and pathologic aggregation have not yet been characterized. In this study, we expressed human recombinant TDP-43 and a truncated splice variant, TDP-S6, in HEK-293 cells and primary neurons. The full-length protein was expressed almost exclusively in the nucleus where it co-localized with endogenous TDP-43. In sharp contrast, the shorter TDP-S6 formed highly ...
A landmark in research on neurodegenerative diseases was the report in 2006 of a protein called TDP-43 as being a major component of protein aggregates in frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). Subsequently, Julien and colleagues made the unexpected discovery that an overproduction of TDP-43, such as detected in ALS, can drive exaggerated activation of the nuclear factor-kB (NF-kB), a key regulator of genes involved in innate immunity.. From these results, we propose to develop a novel therapeutic approach based on production of single chain antibodies, called nanobodies, against TDP-43 that will disrupt interaction between TDP-43 and NF-kB. The first objective will be to derive recombinant antibodies (nanobodies) from the mRNA of cell lines producing antibodies against TDP-43 and to test their ability to block TDP-43 binding to NF-kB. Transfection studies in cultured cells will be carried out to determine the ability of vectors encoding nanobodies to ...
TAR DNA-binding protein 43 kDa (TDP-43), encoded by TARDBP, is an RNA-binding protein, the nuclear depletion of which is the histopathological hallmark of amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disorder affecting both upper and lower motor neurons. Besides motor symptoms, patients with ALS often develop nonneuronal signs including glucose intolerance, but the underlying pathomechanism is still controversial, i.e., whether it is impaired insulin secretion and/or insulin resistance. Here, we showed that ALS subjects reduced early-phase insulin secretion and that the nuclear localization of TDP-43 was lost in the islets of autopsied ALS pancreas. Loss of TDP-43 inhibited exocytosis by downregulating CaV1.2 calcium channels, thereby reducing early-phase insulin secretion in a cultured β cell line (MIN6) and β cell-specific Tardbp-knockout mice. Overexpression of CaV1.2 restored early-phase insulin secretion in Tardbp-knocked-down MIN6 cells. Our findings suggest that TDP-43 ...
TAR DNA-binding protein 43 kDa (TDP-43), encoded by TARDBP, is an RNA-binding protein, the nuclear depletion of which is the histopathological hallmark of amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disorder affecting both upper and lower motor neurons. Besides motor symptoms, patients with ALS often develop nonneuronal signs including glucose intolerance, but the underlying pathomechanism is still controversial, i.e., whether it is impaired insulin secretion and/or insulin resistance. Here, we showed that ALS subjects reduced early-phase insulin secretion and that the nuclear localization of TDP-43 was lost in the islets of autopsied ALS pancreas. Loss of TDP-43 inhibited exocytosis by downregulating CaV1.2 calcium channels, thereby reducing early-phase insulin secretion in a cultured β cell line (MIN6) and β cell-specific Tardbp-knockout mice. Overexpression of CaV1.2 restored early-phase insulin secretion in Tardbp-knocked-down MIN6 cells. Our findings suggest that TDP-43 ...
TAR DNA-binding protein 43 kDa (TDP-43), encoded by TARDBP, is an RNA-binding protein, the nuclear depletion of which is the histopathological hallmark of amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disorder affecting both upper and lower motor neurons. Besides motor symptoms, patients with ALS often develop nonneuronal signs including glucose intolerance, but the underlying pathomechanism is still controversial, i.e., whether it is impaired insulin secretion and/or insulin resistance. Here, we showed that ALS subjects reduced early-phase insulin secretion and that the nuclear localization of TDP-43 was lost in the islets of autopsied ALS pancreas. Loss of TDP-43 inhibited exocytosis by downregulating CaV1.2 calcium channels, thereby reducing early-phase insulin secretion in a cultured β cell line (MIN6) and β cell-specific Tardbp-knockout mice. Overexpression of CaV1.2 restored early-phase insulin secretion in Tardbp-knocked-down MIN6 cells. Our findings suggest that TDP-43 ...
Amyotrophic lateral sclerosis (ALS) occurs as both an inherited disease (~10 percent of cases) and a sporadic disease (~90 percent of cases), implying the contribution of both genetic and environmental/aging-dependent factors to overall risk (Mackenzie et al., 2010). In both forms of the disease, patients display a deposition of TAR DNA-binding protein (TDP)-43 aggregates in the cytoplasm of cells with a concomitant depletion from the nucleus, indicating that TDP-43 protein may be of central importance to disease development. Nevertheless, a main question in the field is whether ALS results from loss of function of wild-type TDP-43 as it is misfolded and incorporated into aggregates, or gain of toxic function from formation of the inclusions. Thus efforts to ameliorate ALS symptoms, as always, must begin with an understanding of TDP-43 function that is illuminated by basic science research. With this in mind, Ling et al. have reported that TDP-43 normally contributes to the fidelity of pre-mRNA ...
Cells robustly reprogram gene expression during stress generated by protein misfolding and aggregation. In this condition, cells assemble the bulk of mRNAs into translationally silent stress granules, while they sustain the translation of specific mRNAs coding for proteins that are needed to overcome cellular stress. Alterations of this process are deeply associated to neurodegeneration. This is the case of amyotrophic lateral sclerosis (ALS), a neurodegenerative disorder caused by a selective loss of motor neurons. Indeed, impairment of protein homeostasis as well as alterations of RNA metabolism are now recognized as major players in the pathogenesis of ALS. In particular, evidence shows that defective mRNA transport and translation are implicated. Here, we provide a review of what is currently known about altered mRNA translation in ALS and how this impacts on the ability of affected cells to cope with proteotoxic stress.
Abstract. Proteinopathy is a collective term used to classified neurodegenerative diseases associated with the progressive accumulation of toxic protein molecules in specific brain regions. Alzheimers disease (AD) is a well-known proteinopathy characterize by the accumulation of A peptides and tau proteins. The accumulation of these toxic molecules in the brain starts many years before any clinical presentation, being the onset in the range of 65 to 72 years of age. Therefore, age is considered a risk factor due, in part, to the loss of molecular competence to clear the brain from these toxic protein molecules. This fact, supported by years of research, demonstrates that brain cells activate a neuroprotective mechanism upon detection of a pathobiological signal that (if the detrimental conditions persist) precedes the activation of the neurodegeneration pathway. The progressive brain region specific neuronal death in neurodegenerative diseases also indicates that the transition from ...
Abstract. Proteinopathy is a collective term used to classified neurodegenerative diseases associated with the progressive accumulation of toxic protein molecules in specific brain regions. Alzheimers disease (AD) is a well-known proteinopathy characterize by the accumulation of A peptides and tau proteins. The accumulation of these toxic molecules in the brain starts many years before any clinical presentation, being the onset in the range of 65 to 72 years of age. Therefore, age is considered a risk factor due, in part, to the loss of molecular competence to clear the brain from these toxic protein molecules. This fact, supported by years of research, demonstrates that brain cells activate a neuroprotective mechanism upon detection of a pathobiological signal that (if the detrimental conditions persist) precedes the activation of the neurodegeneration pathway. The progressive brain region specific neuronal death in neurodegenerative diseases also indicates that the transition from ...
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In this study, we update the TDP-43 in Alzheimers disease staging scheme by assessing the topography of TDP-43 in 193 cases of Alzheimers disease, in 14 different brain regions (eight previously described plus six newly reported) and use conditional probability to model the spread of TDP-43 across …
The goal of the following team assignment is for students to gain hands-on experience by working on recently published RNA-seq data and apply the concepts they have learned up to RNA alignment. To complete this assignment, students will need to review commands we performed in earlier sections. Background on Dataset used In this assignment, we will be using subsets of the GSE136366 dataset (Roczniak-Ferguson A, Ferguson SM. Pleiotropic requirements for human TDP-43 in the regulation of cell and organelle homeostasis. Life Sci Alliance 2019 Oct;2(5). PMID: 31527135). This dataset consists of 6 RNA sequencing files of human cells that either express or lack the TDP-43 protein. Experimental Details The libraries are prepared as paired end. The samples are sequenced on a Illuminas HiSeq 2500. Each read is 70 bp long The dataset is located here: GSE136366 3 samples from TDP-43 Knockout HeLa cells and 3 samples wherein a wildtype TDP-43 transgene was re-expressed. For this exercise we will be using different
In a non-disease state, TDP-43 is an important protein involved in various aspects of the metabolism of RNA, a molecule essential in various biological roles in the regulation and expression of genes. In a disease state, several mutations in TDP-43 have been identified as a cause of some hereditary and sporadic ALS and FTD cases. While this underscores the critical role of TDP-43 in the development of these conditions, the specific effect of aging on TDP-43 has not been investigated. This prompted a team of scientists centered in Nagoya, Japan, to delve deep into the subject. Their findings were recently published in Scientific Reports ...
A long term project you have worked on during your time at the IoN is the therapeutic potential of a novel drug called Arimoclomol. Arimoclomol seems to be widely applicable to many diseases - youve done studies with it in the MNDs ALS and SBMA, and most recently in the muscle disorder IBM. Can you tell me why this is so widely applicable? Diseases are really characterized by their clinical manifestation, and how clinicians define them. IBM, FTD and ALS have been previously considered to be completely different diseases. However, that doesnt mean that the underlying pathological mechanisms or causes are in fact completely different. For example, multisystem proteinopathy is a disease caused by mutations on one gene, VCP, but the disease can manifest as IBM in the muscle, ALS in the CNS or FTD in the brain- or indeed a combination of all three diseases, but in each of the specific tissues affected, a common pathological characteristic is protein mishandling - and this is precisely the process ...
The 43 kDa TAR DNA binding protein (TDP-43) has been identified as one of the major proteins that accumulates in the cytoplasm of brain and spinal cord from the patients affected with amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Under basal conditions, TDP-43 localizes in nucleus functioning as an RNA binding protein to regulate different aspects of RNA metabolism, such as alternative splicing of messenger RNA. In ALS/FTLD brains and spinal cords, TDP-43 forms well-defined cytoplasmic granules, the behavior very similar to stress granule (SG) proteins, but the mechanisms are poorly understood. To investigate the mechanism of TDP-43 granule formation and to identify potential therapeutic targets by inhibiting the granule formation, our laboratory screened a chemical library of 75,000 compounds using the inducible PC12 cells that express EGFP-tagged wild-type human TDP-43. We used the biological effect of cycloheximide on SGs as a basis for the screen, since it ...
To determine the identity of the 24- and 26-kD protein bands recognized by mAbs 182 and 406, respectively, we performed two-dimensional polyacrylamide gel electrophoresis (2D PAGE) immunoblots by using urea fractions from types 1 and 2 brains. MAbs 182 and 406 immunolabeled protein spots ∼25 kD with a pI ∼3.5 (fig. S1, A and C). The same spots were identified on duplicate Coomassie Blue-stained 2D PAGE gels (fig. S1, B and D) and analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The same three peptides corresponding to amino acid residues 252 to 263, 276 to 293, and 409 to 414 of the TAR-DNA-binding protein 43 (TDP-43) were identified (Fig. 1F). Notably, the 409-414 peptide is at the extreme C terminus of TDP-43, suggesting that both 24- and 26-kD fragments are truncated in the middle of TDP-43 and extend to its C terminus.. The human gene encoding TDP-43 (TARDP) on chromosome 1 was cloned and shown to bind a polypyrimidine-rich motif in the HIV transactive response DNA ...
TY - JOUR. T1 - Curcumin abolishes mutant TDP-43 induced excitability in a motoneuron-like cellular model of ALS. AU - Dong, H.. AU - Xu, L.. AU - Wu, L.. AU - Wang, X.. AU - Duan, W.. AU - Li, H.. AU - Li, C.. PY - 2014/7/11. Y1 - 2014/7/11. N2 - Mutation of TAR DNA-binding protein-43 (TDP-43) is detected in familial and sporadic amyotrophic lateral sclerosis (FALS and SALS). TDP-43-positive cytoplasmic inclusions are present in both neuron and glia of ALS, although not in mutant Cu/Zn-superoxide dismutase (mSOD1)-related or RNA binding protein Fused in sarcoma (FUS)-related ALS. Previous studies have established that cortical hyper-excitability is common to both FALS and SALS patients. Much of our current understanding of neuron excitability has come from studying the subtype of mSOD1-related ALS. Thus, we evaluated the excitable capability through analyzing properties of action potentials (APs) and voltage-gated sodium (Na v ) channels on the cellular model, motoneuron-like cell lines that ...
Background Frontotemporal lobar degeneration (FTLD) is most commonly associated with TAR-DNA binding protein (TDP-43) or tau pathology at autopsy, but there are no in vivo biomarkers reliably discriminating between sporadic cases. As disease-modifying treatments emerge, it is critical to accurately identify underlying pathology in living patients so that they can be entered into appropriate etiology-directed clinical trials. Patients with tau inclusions (FTLD-TAU) appear to have relatively greater white matter (WM) disease at autopsy than those patients with TDP-43 (FTLD-TDP). In this paper, we investigate the ability of white matter (WM) imaging to help discriminate between FTLD-TAU and FTLD-TDP during life using diffusion tensor imaging (DTI).. ...
The ubiquitin-proteasome system degrades most intracellular proteins, including misfolded proteins. Proteasome functional insufficiency (PFI) was observed in experimental proteinopathies and implicated in many human common diseases but its pathogenic role has not been established because a measure to enhance proteasome function in the cell has not been reported until very recently. We have recently discovered that overexpression of proteasome activator 28α (PA28α) enhances proteasome-mediated removal of abnormal proteins in the cell and protects against oxidative stress in cultured cardiomyocytes (FASEB J 2011; 25(3):883-93). Here we have extended the in vitro discoveries to intact animals. First, we created inducible transgenic mice with cardiomyocyte-restricted PA28α overexpression (CR-PA28αOE). CR-PA28αOE does not alter the homeostasis of normal proteins and cardiac function but increases the degradation of a surrogate misfolded protein in the heart. This marks the establishment of the ...
The transactive response DNA binding protein (TDP-43) has long been characterized as a main hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitin-positiv
The cytoplasmic aggregation of TAR DNA-binding protein-43 (TDP-43) is a hallmark of degenerating neurons in amyotrophic lateral sclerosis (ALS) and subsets of frontotemporal dementia (FTD). In order to reduce TDP-43 pathology, we generated single-chain (scFv) antibodies against the RNA recognition motif 1 (RRM1) of TDP-43, which is involved in abnormal protein self-aggregation and interaction with p65 NF-κB. Virus-mediated delivery into the nervous system of a scFv antibody, named VH7Vk9, reduced microgliosis in a mouse model of acute neuroinflammation and mitigated cognitive impairment, motor defects, TDP-43 proteinopathy, and neuroinflammation in transgenic mice expressing ALS-linked TDP-43 mutations. These results suggest that antibodies targeting the RRM1 domain of TDP-43 might provide new therapeutic avenues for the treatment of ALS and FTD.. ...
Communication between neurons and glia is essential for development and function of the nervous system, and dysregulation of these bidirectional pathways leads to neuropathologies. Neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD), are often characterized by reactive astrocytes that are neurotoxic or show reduced neuroprotective activity, thus promoting neuron loss. To identify factors that confer neurotoxicity to reactive glia, Bi et al. surveyed factors secreted from forebrain slices from rats in which microglia and astrocytes were activated by transgenically expressing an ALS-associated allele of the TAR DNA-binding protein 43 (TDP-43) in the forebrain. In the TDP-43 model, transgenic rats developed FTLD or motor neuron degeneration similar to ALS, depending on the timing of transgene induction. After controlling for the glial reactivity that normally accompanies brain slice culture, the authors identified lipocalin 2 (lcn2) ...
Toda la información sobre las últimas publicaciones científicas de la Clínica Universidad de Navarra. Ubiquitin associated protein 1 is a risk factor for frontotemporal lobar degeneration
DESCRIPTION (provided by applicant): Amyotrophic lateral sclerosis (ALS) is a devastating disease affecting about 2 in 100,000 people in the USA each year. Recent discoveries have the potential to dramatically change our understanding of the causes of ALS and identification of possible targets for treatment. ALS results from the selective loss of motor neurons, which in ALS patients contain cytoplasmic aggregates of proteins. Identification that a major constituent of these aggregates is the RNA-binding protein TDP-43, which is normally localized in the nucleus, has opened up many new directions in ALS research. A large number of mutations in TDP-43 have also been identified in ALS patients providing a causative link between this protein and the disease. TDP-43 aggregates have also been identified in post-mortem samples of patients who have died of other neurodegenerative diseases such as fronto-temporal dementias, Alzheimers and Parkinsons diseases, suggesting that TDP-43 pathology might be a ...
The classification of neurodegenerative disorders is based on the major component of the protein aggregates in the brain. The most common altered proteins associated with neurodegeneration are Hyperphosphorylated tau (HPt), beta amyloid (Aβ), alpha-synclein (αS) and transactive response DNA binding protein 43 (TDP43). In this study we assessed the incidence and the neuroanatomical distribution of proteins associated with neurodegeneration in the brain tissue of cognitively unimpaired subjects.. We demonstrated the early involvement of the Locus Coeruleus (LC) with HPt pathology in cognitively unimpaired mid aged subjects, a finding which supports the notion that LC is an initiation site of HPt pathology. This may suggest that development of clinical assessment techniques and radiological investigations reflecting early LC alterations may help in identifying subjects with early stages of neurodegeneration.. Furthermore, we studied a large cohort of cognitively unimpaired subjects with age at ...
AbstractNuclear depletion of TDP-43, an essential RNA binding protein, may underlie neurodegeneration in amyotrophic lateral sclerosis (ALS). As several functions have been ascribed to this protein, the critical role(s) of TDP-43 in motor neurons that may be compromised in ALS remains unknown. We show here that TDP-43 mediated splicing repression, which serves to protect the transcriptome by preve...
Trans-synaptic spread of the protein pathology mechanistically links the stereotyped progression of PD from SNc to the frontal cortex through anatomically interconnected pathways. One argument for the prion-like behaviour of α-syn comes from the LB pathology of embryonic grafts of dopaminergic cells implanted in the midbrain, suggesting local spread of LB from host SNc neurons with high LB burden.79-81 The converging pathology of several synucleinopathies and other proteinopathies strongly supports trans-synaptic spread to both frontal and autonomic centres in both rostral and caudal directions. What is the cellular basis for α-syn spreading pathology? Work done in the last decade demonstrates the prion-like features of α-syn and other amyloids.82-84 For decades, prion diseases enjoyed a unique, defining feature: transmissibility. But at the molecular level, all amyloids share significant structural, biochemical and biological features.65 85 All amyloids aggregate by templated seeded ...
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The RNA binding protein TDP-43 is a major constituent of proteinaceous granules observed in brain tissue of patients suffering from a diverse spectrum of neurological diseases including ALS, AD and CTE. RNA is known to influence the mechanisms by which TDP-43 and other similarly dynamic, intrinsically disordered, proteins undergo liquid-liquid phase separation and pathological aggregation. The lab is interested in understanding the biophysical basis for TDP-43 aggregation and details regarding how RNA influences in vitro and in vivo phase-separation and corresponding pathogenicity. Our ultimate goal is to provide proof-of-concept data for new types of RNA medicines to combat these currently untreatable diseases. ...
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Agregati proteina TDP-43 so prisotni v pogostih nevrodegeneracijskih boleznih. Prvo odkritje vloge tega proteina je bilo objavljeno leta 20062, ravno v letu, ko sem vzpostavil svojo raziskovalno skupino v Laboratoriju za molekularno biologijo (LMB) v Cambridgeu. Pred tem sem razvil tehniko CLIP3, s katero se določi molekule RNK, ki jih nek protein regulira v živih celicah. Možgansko tkivo se vzpostavi ultravijolični svetlobi, ki povzroči tvorbo kovalentnih vezi med proteini in molekulami RNK. Tako se nekako zamrzne molekularna slika živih celic, in nato se uporabijo različni biokemijski prostopi za izolacijo in prepoznavo RNK vezavnih mest. Ko sem debatiral s svojim prvim doktorskim študentom, Jamesom Tollervejem, sva se strinjala, da bi bil TDP-43 pravi protein za preučevanje. Poleg tega se nama je zdelo posebej zanimivo, da bi delala s človeškim možganskim tkivom, saj bi tako dobila povsem nov pogled v molekularna dogajanja v človeških možganih.. Po srečnem naključju je ob ...
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