• neurons
  • The authors also stained postmortem tissue from 10 people who had died of ALS with antibodies for the HERV-K envelope protein and detected binding in cortical large pyramidal neurons and spinal cord anterior-horn neurons. (alzforum.org)
  • Recent work has characterized the transcriptome-wide binding sites revealing that thousands of RNAs are bound by TDP-43 in neurons. (wikipedia.org)
  • The collaborative research team confirmed that different kinds of cryptic exons were produced depending on the cell types such as muscle cells and neurons after an experiment using gene-manipulated mice that were prevented from expressing Tdp-43 protein in the desired cells. (eurekalert.org)
  • Recently, TAR DNA-binding protein 43 (TDP-43) has been found to be a principal component of ubiquitinated cytoplasmic inclusions in neurons and glia in ALS. (springer.com)
  • The recent study has found that thousands of transcribed binding sites of RNAs are bound by TDP-43 in neurons [ 2 ]. (ijbs.com)
  • TDP-43 also is a responsive factor of neuronal activity in the dendrites of hippocampal neurons, is suggested that its possible roles is to regulate the stability, transport and local translation of mRNA in neurons [ 5 ]. (ijbs.com)
  • His research examines molecular and cellular aspects of disease, and utilizes a variety of transgenic models including mice, C. elegans, primary neurons and cell lines. (wikipedia.org)
  • The Wolozin laboratory has extended this work to explain the pathophysiology of Alzheimer's disease Work from the Wolozin laboratory demonstrates that the pathology occurring in neurons (neurofibrillary tangles) is associated with RNA binding proteins. (wikipedia.org)
  • genes
  • Tdp-43 is a protein that regulates the process of making proteins from genes. (eurekalert.org)
  • The transcription of the artJ, artPIQM and hisJQMP genes and operons is repressed by liganded ArgR, whereas argT, encoding the LAO (lysine, arginine, ornithine) periplasmic binding protein, is insensitive to the repressor. (naver.com)
  • Although these ALS associated genes, including RNA-binding protein (TDP-43), autophagy adaptor (UBQLN2), and a possible C9ORF72, have vastly different cellular functions in the typical clinical phenotype, mutations of these genes can all result in ALS. (springer.com)
  • Our long-term goal is to identify the critical genes and cellular pathways affected by misfolded human disease proteins. (stanford.edu)
  • 1. The genes and pathways that are able to modify TDP-43 toxicity in yeast are now good candidates for evaluation as genetic contributors to ALS and related disorders in humans (e.g., see ataxin 2 below). (stanford.edu)
  • In this study we sought to identify genes and cellular processes that are involved in the toxicity conferred by the defective ALS8 allele. (plos.org)
  • In 1994, Stuart L. Schreiber, David M. Sabatini and Robert T. Abraham independently discovered a protein that directly interacts with FKBP12-rapamycin, which became known as mTOR due to its homology to the yeast TOR/DRR genes. (wikipedia.org)
  • Sequence analysis of mTOR revealed it to be the direct ortholog of proteins encoded by the yeast target of rapamycin 1 and 2 (TOR1 and TOR2) genes, which Joseph Heitman, Rao Movva, and Michael N. Hall had identified in August 1991 and May 1993. (wikipedia.org)
  • Determining the biological steps in the embryonic development of the human heart to identify genes, RNAs or proteins that can be targeted to treat congenital heart disease. (wikipedia.org)
  • proteinopathies
  • Spinocerebellar ataxia type 1 (SCA1) endoplasmic reticulum (ER), (as seen with neuroserpin mutations that cause familial encephalopathy with neuroserpin inclusion bodies) extracellularly excreted proteins, amyloid-β in Alzheimer's disease There are two main avenues eukaryotic cells use to remove troublesome proteins or organelles: ubiquitin-proteasome: protein ubiquitin along with enzymes is key for the degradation of many proteins that cause proteinopathies including polyQ expansions and alpha-synucleins. (wikipedia.org)
  • The proteopathies (also known as proteinopathies, protein conformational disorders, or protein misfolding diseases) include such diseases as Creutzfeldt-Jakob disease and other prion diseases, Alzheimer's disease, Parkinson's disease, amyloidosis, and a wide range of other disorders (see List of Proteopathies). (wikipedia.org)
  • gene
  • Abhyankar MM, Urekar C, Reddi PP (2007) A novel CpG-free vertebrate insulator silences the testis-specific SP-10 gene in somatic tissues: role for TDP-43 in insulator function. (springer.com)
  • Buratti E, Baralle FE (2008) Multiple roles of TDP-43 in gene expression, splicing regulation, and human disease. (springer.com)
  • In addition, this protein regulates alternate splicing of the CFTR gene. (wikipedia.org)
  • In Escherichia coli L-arginine is taken up by three periplasmic binding protein-dependent transport systems that are encoded by two genetic loci: the artPIQM-artJ and argT-hisJQMP gene clusters. (naver.com)
  • Uchida's team found that the von Hippel Lindau (VHL) protein-associated with a gene most notable for cancer suppression-strongly binds to malformed versions of TDP-43 in oligodendrocytes. (technologynetworks.com)
  • The protein of TDP-43 was also shown to modulate the splicing of the gene of CFTR and apoA-II. (ijbs.com)
  • The mechanistic target of rapamycin (mTOR), also known as the mammalian target of rapamycin and FK506-binding protein 12-rapamycin-associated protein 1 (FRAP1), is a kinase that in humans is encoded by the MTOR gene. (wikipedia.org)
  • The UBQLN2 gene encodes production of the protein ubiquilin 2 in the cell, which is a member of the ubiquilin family and controls the degradation of ubiquitinated proteins. (wikipedia.org)
  • Since the TBK1 protein is haploinsufficient, meaning mutations in the gene result in no protein production. (wikipedia.org)
  • The SMN1 gene produces a complete transcript, while SMN2 produces a transcript without exon 7 which results in a truncated protein. (wikipedia.org)
  • Survival of motor neuron 2 (SMN2) is a gene that encodes the SMN protein (full and truncated) in humans. (wikipedia.org)
  • The telomeric (SMN1) and centromeric (SMN2) copies of this gene are nearly identical and encode the same protein. (wikipedia.org)
  • Alzheimer's
  • HERV-K protein was absent from the brain tissue of 10 people who died of Alzheimer's disease. (alzforum.org)
  • Amador-Ortiz C, Lin WL, Ahmed Z et al (2007) TDP-43 immunoreactivity in hippocampal sclerosis and Alzheimer's disease. (springer.com)
  • Arai T, Mackenzie IR, Hasegawa M et al (2009) Phosphorylated TDP-43 in Alzheimer's disease and dementia with Lewy bodies. (springer.com)
  • Abnormalities of TDP-43 also occur in an important subset of Alzheimer's disease patients, correlating with clinical and neuropathologic features indexes. (wikipedia.org)
  • Encouraged by the power of the yeast system to gain insight into α-synuclein biology, we are creating new yeast models to study additional protein-misfolding disorders, including Alzheimer's disease and ALS. (stanford.edu)
  • Unlike Alzheimer's disease, which is associated with several brain factors, FTLD diseases arise only with a malfunction of a single protein. (dana.org)
  • In 1986 he identified the antibody Alz-50, which was one of the first antibodies to identify the conformation specific epitopes of microtubule associated protein tau that are abundant in the brains of patients suffering from Alzheimer's disease. (wikipedia.org)
  • exon
  • Ayala YM, Pagani F, Baralle FE (2006) TDP43 depletion rescues aberrant CFTR exon 9 skipping. (springer.com)
  • Buratti E, Baralle FE (2001) Characterization and functional implications of the RNA binding properties of nuclear factor TDP-43, a novel splicing regulator of CFTR exon 9. (springer.com)
  • A particular mutation occurs in the CFTR pre-mRNA and leads to the exclusion of exon 9, mRNA lacking this exon folds a truncated protein (a protein shortened by a mutation). (wikipedia.org)
  • The TDP-43 protein is responsible for physically silencing the exon splicing site once it is recruited by the exonic splicing silencer (TG)mT(n). (wikipedia.org)
  • The UAGACA ESS is thought to work by disrupting an exonic splicing enhancer and attracting proteins that inhibit splicing by binding sequences on exon 7. (wikipedia.org)
  • The inclusion of the cryptic exon results in protein truncation and atypical splicing patterns. (wikipedia.org)
  • mutations
  • Mutations in the human VAMP-associated protein B (hVAPB) cause a heterogeneous group of motor neuron diseases including ALS8. (plos.org)
  • In line with that, I show that ALS-associated FUS mutations result in cytosolic mislocalization of FUS that is upon subsequent cellular stress sequestered into SGs. (uni-muenchen.de)
  • Mutations in UBQLN2 interfere with protein degradation, leading to neurodegeneration and causing dominantly inherited, chromosome X-linked ALS and ALS/dementia. (wikipedia.org)
  • In 2016, it was observed that mutations in the TBK1 protein contributed to formation of the disease. (wikipedia.org)
  • RNAs
  • Stress granules are dense aggregations in the cytosol composed of proteins & RNAs that appear when the cell is under stress. (wikipedia.org)
  • induce
  • All known prions induce the formation of an amyloid fold, in which the protein polymerises into an aggregate consisting of tightly packed beta sheets. (wikipedia.org)
  • transgenic
  • We examined the TDP-43 expression and distribution in the different anatomic regions, segments and neural cells in the adult spinal cord at the different stages of the SOD1 wild-type and G93A transgenic model by the fluorescent immunohistochemical technology. (ijbs.com)
  • Fragments
  • In this thesis I demonstrate that cytosolically mislocalized full-length TDP-43 is recruited into SGs, whereas C-terminal fragments of TDP-43 (TDP-CTFs) fail to localize to SGs. (uni-muenchen.de)
  • nuclear
  • Here, I provide evidence that this cytosolic deposition of FET proteins can be mimicked in cultured cells by inhibition of Transportin-mediated nuclear import, which causes cytosolic mislocalization of all FET proteins and recruitment of these proteins in SGs. (uni-muenchen.de)
  • Diseases
  • Scientists expect to elucidate pathogenic mechanisms of Frontotemporal Dementia (FTD) and other diseases once they find how Tdp-43 protein and cryptic exons* interact with each other depending on the cellular context. (eurekalert.org)
  • Recent studies have implied that the misfolding and accumulation of the protein TDP-43 in oligodendrocytes was likely linked to the development of ALS, as with other neurological diseases like Alpha-synuclein in Parkinson's. (technologynetworks.com)
  • We use the baker's yeast, Saccharomyces cerevisiae, as a model system to study the cell biology underpinning protein-misfolding diseases like Parkinson's disease and ALS. (stanford.edu)
  • For each FTLD disease, knowing where the protein problem originates in the brain, how the ensuing degenerative process spreads in the brain, and whether these patterns differ among FTLD diseases should substantially improve the ability to develop therapies that can arrest disease progression. (dana.org)
  • As research progresses, many similarities appear that relate these diseases to one another on a sub-cellular level. (wikipedia.org)
  • Since 2008, Dr. Wolozin's research has focused on the role of RNA binding proteins and stress granules in neurodegenerative diseases. (wikipedia.org)
  • It is hypothesized that chaperones and co-chaperones (proteins that assist protein folding) may antagonize proteotoxicity during aging and in protein misfolding-diseases to maintain proteostasis. (wikipedia.org)
  • Prions composed of the prion protein (PrP) are believed to be the cause of transmissible spongiform encephalopathies (TSEs) among other diseases. (wikipedia.org)
  • The most relevant epigenetic modifications to treatment of neurodegenerative diseases are DNA methylation and histone protein modifications via methylation or acetylation. (wikipedia.org)
  • spinal cord
  • The amount of TDP-43 positive cell significantly increased at the onset and progression stages of ALS following with the increase of neuron death in spinal cord, particularly in the ventral horn of cervical segment at the progression stage. (ijbs.com)
  • Additionally
  • Additionally, I found that both proteins have the same requirements for SG recruitment, as their main RNA-binding domain and a glycine-rich domain are essential for SG localization. (uni-muenchen.de)
  • yeast
  • Since dealing with misfolded proteins is an ancient problem, we hypothesize that the mechanisms employed to cope with them are likely conserved from yeast to man. (stanford.edu)
  • We recently developed a yeast model to study the ALS disease protein TDP-43 (Johnson et al. (stanford.edu)
  • Interestingly, one of the hits from our yeast TDP-43 genetic modifier screen, PBP1, is the homolog of a human neurodegenerative disease protein, ataxin 2. (stanford.edu)
  • Because of these different names, mTOR, which had been first used by Robert T. Abraham, was increasingly adopted by the community of scientists working on the mTOR pathway to refer to the protein and in homage to the original discovery of the TOR protein in yeast that was named TOR, the Target of Rapamycin, by Joe Heitman, Rao Movva, and Mike Hall. (wikipedia.org)
  • Several yeast proteins have also been identified as having prionogenic properties. (wikipedia.org)
  • In yeast, this refolding is assisted by chaperone proteins such as Hsp104. (wikipedia.org)
  • Exons
  • Cryptic exons are regions of the genome that are normally skipped by the spliceosome due to the presence of adjacent UG microsatellite repeats, the consensus binding site of Tdp-43. (eurekalert.org)
  • Tdp-43 Cryptic Exons are Highly Variable between Cell Types," Molecular Neurodegeneration 2017. (eurekalert.org)
  • amino
  • These include destabilizing changes in the primary amino acid sequence of the protein, post-translational modifications (such as hyperphosphorylation), changes in temperature or pH, an increase in production of a protein, or a decrease in its clearance. (wikipedia.org)
  • DNA methylation occurs on the cytosine of CpG dinucleotides in the genomic sequence, and protein methylation occurs on the amino termini of the core histone proteins - most commonly on lysine residues (Bradley et al. (wikipedia.org)
  • Molecular
  • Molecular and Cellular Neuroscience. (wikipedia.org)
  • We are now using these models to perform high-throughput genetic and small molecule screens to elucidate the molecular pathways that regulate the function of these disease proteins and control their conversion to a pathological conformation. (stanford.edu)
  • The stress proteins that are the main component of stress granules in plant cells are molecular chaperones that sequester, protect, and possibly repair proteins that unfold during heat and other types of stress. (wikipedia.org)
  • In nearly all instances, the disease-causing molecular configuration involves an increase in beta-sheet secondary structure of the protein. (wikipedia.org)
  • Francis Crick recognized the potential significance of the Griffith protein-only hypothesis for scrapie propagation in the second edition of his "Central dogma of molecular biology" (1970): While asserting that the flow of sequence information from protein to protein, or from protein to RNA and DNA was "precluded", he noted that Griffith's hypothesis was a potential contradiction (although it was not so promoted by Griffith). (wikipedia.org)
  • modifiers
  • We are currently analyzing hits from recent high-throughput screens that identified potent modifiers of TDP-43 toxicity. (stanford.edu)
  • Surprisingly, the list of modifiers was mostly enriched for proteins linked to lipid droplet biogenesis and dynamics. (plos.org)
  • interacts
  • Moreover, we observed that mutant SOD1 interacts with TDP-43 in co-immunoprecipitation assays with G93A hSOD1-transfected cell lines. (springer.com)
  • Insulin
  • As a core component of mTORC2, mTOR also functions as a tyrosine protein kinase that promotes the activation of insulin receptors and insulin-like growth factor 1 receptors. (wikipedia.org)
  • Structural
  • Because proteins share a common structural feature known as the polypeptide backbone, all proteins have the potential to misfold under some circumstances. (wikipedia.org)
  • However, only a relatively small number of proteins are linked to proteopathic disorders, possibly due to structural idiosyncrasies of the vulnerable proteins. (wikipedia.org)
  • phenotype
  • Importantly, the resulting recombinant product lacks functional RNA recognition motifs (RRMs) and, thus, does not have specific TDP-43-physiological functions (i.e. splicing regulation ability) that might affect the animal phenotype per se. (biologists.org)
  • interactions
  • These findings suggest that mutant SOD1 could affect the solubility/insolubility of TDP-43 through physical interactions and the resulting pathological modifications of TDP-43 may be involved in motor neuron death in SOD1 fALS. (springer.com)
  • induces
  • Others result when a protein called "Tau" misfolds in brain cells and induces Tau in nearby brain cells to similarly misfold, eventually blocking cellular communication and causing cells to die. (dana.org)
  • When a prion enters a healthy organism, it induces existing, properly folded proteins to convert into the misfolded prion form. (wikipedia.org)
  • complexes
  • mTOR links with other proteins and serves as a core component of two distinct protein complexes, mTOR complex 1 and mTOR complex 2, which regulate different cellular processes. (wikipedia.org)
  • The RNA molecules stored are stalled translation pre-initiation complexes: failed attempts to make protein from mRNA. (wikipedia.org)
  • prion disease
  • They have been most thoroughly studied with regard to prion disease, and are referred to as protein strains. (wikipedia.org)
  • The best known form of such inducible proteopathy is prion disease, which can be transmitted by exposure of a host organism to purified prion protein in a disease-causing conformation. (wikipedia.org)
  • associate
  • We have validated this genetic interaction in the fly nervous system (in collaboration with Nancy Bonini at PENN), used biochemistry to show the proteins physically associate in an RNA-dependent manner. (stanford.edu)
  • Stress granules and processing bodies share RNA and protein components, both appear under stress, and can physically associate with one another. (wikipedia.org)
  • LLPS occurs when RNA binding proteins associate to form structures analogous to liquid droplets, which separate from surrounding aqueous medium. (wikipedia.org)
  • stress granules
  • Therefore, any association of mRNAs with stress granules may simply be a side effect of the association of partially unfolded RNA-binding proteins with stress granules, similar to the association of mRNAs with proteasomes. (wikipedia.org)
  • Environmental stressors trigger cellular signaling which eventually leads to the formation of stress granules. (wikipedia.org)
  • The protein G3BP1 is necessary for the proper docking of processing bodies and stress granules to each other, which may be important for the preservation of polyadenylated mRNAs. (wikipedia.org)
  • Although some protein components are shared between stress granules and processing bodies, the majority of proteins in either structure are uniquely localized to either structure. (wikipedia.org)
  • The complete proteome of stress granules is still unknown, but efforts have been made to catalog all of the proteins that have been experimentally demonstrated to transit into stress granules. (wikipedia.org)
  • Since then, a growing body of evidence, increasingly highlights the important contributions of RNA-binding proteins (RBPs), stress granules and translational regulation in the pathophysiology of neurodegenerative disease. (wikipedia.org)
  • disease
  • however, the role played by TDP-43 in disease onset and progression is still unclear. (biologists.org)
  • Parkinson's disease and Huntington's disease are both late-onset and associated with the accumulation of intracellular toxic proteins. (wikipedia.org)
  • Defining the enzymes involved in triglyceride biosynthesis and the cell biology underlying lipid storage in cells, as a way to understand obesity-related illnesses-such as heart disease and diabetes-at the cellular level. (wikipedia.org)
  • Prions are infectious agents composed entirely of a protein material that can fold in multiple, structurally abstract ways, at least one of which is transmissible to other prion proteins, leading to disease in a manner that is epidemiologically comparable to the spread of viral infection. (wikipedia.org)
  • animals that do not express the normal form of the prion protein can neither develop nor transmit the disease. (wikipedia.org)