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  1. Article ; Online: Think globally, act locally: Centrosome-localized mRNAs ensure mitotic fidelity.

    Zarnescu, Daniela C

    The Journal of cell biology

    2020  Volume 219, Issue 12

    Abstract: The functional importance of mRNA localization to centrosomes is unclear. Ryder et al. (2020. J. Cell Biol. https://doi.org/10.1083/jcb.202004101) identify fragile-X mental retardation protein as a regulator of centrocortin (cen) mRNA dynamics in ... ...

    Abstract The functional importance of mRNA localization to centrosomes is unclear. Ryder et al. (2020. J. Cell Biol. https://doi.org/10.1083/jcb.202004101) identify fragile-X mental retardation protein as a regulator of centrocortin (cen) mRNA dynamics in Drosophila. Mistargeting of cen impairs division and development, indicating that cen mRNA localization to centrosomes ensures mitotic fidelity.
    MeSH term(s) Animals ; Centrosome ; Drosophila/genetics ; Mitosis ; RNA, Messenger/genetics
    Chemical Substances RNA, Messenger
    Language English
    Publishing date 2020-11-20
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S. ; Comment
    ZDB-ID 218154-x
    ISSN 1540-8140 ; 0021-9525
    ISSN (online) 1540-8140
    ISSN 0021-9525
    DOI 10.1083/jcb.202010172
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article: Dysregulation of Translation in TDP-43 Proteinopathies: Deficits in the RNA Supply Chain and Local Protein Production.

    Bjork, Reed T / Mortimore, Nicholas P / Loganathan, Suvithanandhini / Zarnescu, Daniela C

    Frontiers in neuroscience

    2022  Volume 16, Page(s) 840357

    Abstract: Local control of gene expression provides critical mechanisms for regulating development, maintenance and plasticity in the nervous system. Among the strategies known to govern gene expression locally, mRNA transport and translation have emerged as ... ...

    Abstract Local control of gene expression provides critical mechanisms for regulating development, maintenance and plasticity in the nervous system. Among the strategies known to govern gene expression locally, mRNA transport and translation have emerged as essential for a neuron's ability to navigate developmental cues, and to establish, strengthen and remove synaptic connections throughout lifespan. Substantiating the role of RNA processing in the nervous system, several RNA binding proteins have been implicated in both developmental and age dependent neurodegenerative disorders. Of these, TDP-43 is an RNA binding protein that has emerged as a common denominator in amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD) and related disorders due to the identification of causative mutations altering its function and its accumulation in cytoplasmic aggregates observed in a significant fraction of ALS/FTD cases, regardless of etiology. TDP-43 is involved in multiple aspects of RNA processing including splicing, transport and translation. Given that one of the early events in disease pathogenesis is mislocalization from the nucleus to the cytoplasm, several studies have focused on elucidating the pathogenic role of TDP-43 in cytoplasmic translation. Here we review recent findings describing TDP-43 translational targets and potential mechanisms of translation dysregulation in TDP-43 proteinopathies across multiple experimental models including cultured cells, flies, mice and patient derived neurons.
    Language English
    Publishing date 2022-03-07
    Publishing country Switzerland
    Document type Journal Article ; Review
    ZDB-ID 2411902-7
    ISSN 1662-453X ; 1662-4548
    ISSN (online) 1662-453X
    ISSN 1662-4548
    DOI 10.3389/fnins.2022.840357
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article: Lost in Translation: Evidence for Protein Synthesis Deficits in ALS/FTD and Related Neurodegenerative Diseases.

    Lehmkuhl, Erik M / Zarnescu, Daniela C

    Advances in neurobiology

    2018  Volume 20, Page(s) 283–301

    Abstract: Cells utilize a complex network of proteins to regulate translation, involving post-transcriptional processing of RNA and assembly of the ribosomal unit. Although the complexity provides robust regulation of proteostasis, it also offers several ... ...

    Abstract Cells utilize a complex network of proteins to regulate translation, involving post-transcriptional processing of RNA and assembly of the ribosomal unit. Although the complexity provides robust regulation of proteostasis, it also offers several opportunities for translational dysregulation, as has been observed in many neurodegenerative disorders. Defective mRNA localization, mRNA sequatration, inhibited ribogenesis, mutant tRNA synthetases, and translation of hexanucleotide expansions have all been associated with neurodegenerative disease. Here, we review dysregulation of translation in the context of age-related neurodegeneration and discuss novel methods to interrogate translation. This review primarily focuses on amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), a spectrum disorder heavily associated with RNA metabolism, while also analyzing translational inhibition in the context of related neurodegenerative disorders such as Alzheimer's disease and Huntington's disease and the translation-related pathomechanisms common in neurodegenerative disease.
    MeSH term(s) Amyotrophic Lateral Sclerosis/metabolism ; Frontotemporal Dementia/metabolism ; Humans ; Protein Biosynthesis/physiology ; RNA-Binding Proteins/metabolism ; Ribosomes/metabolism
    Chemical Substances RNA-Binding Proteins
    Language English
    Publishing date 2018-06-18
    Publishing country United States
    Document type Journal Article ; Review
    ISSN 2190-5215
    ISSN 2190-5215
    DOI 10.1007/978-3-319-89689-2_11
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Measuring Glucose Uptake in Drosophila Models of TDP-43 Proteinopathy.

    Loganathan, Suvithanandhini / Ball, Hannah E / Manzo, Ernesto / Zarnescu, Daniela C

    Journal of visualized experiments : JoVE

    2021  , Issue 174

    Abstract: Amyotrophic lateral sclerosis is a neurodegenerative disorder causing progressive muscle weakness and death within 2-5 years following diagnosis. Clinical manifestations include weight loss, dyslipidemia, and hypermetabolism; however, it remains unclear ... ...

    Abstract Amyotrophic lateral sclerosis is a neurodegenerative disorder causing progressive muscle weakness and death within 2-5 years following diagnosis. Clinical manifestations include weight loss, dyslipidemia, and hypermetabolism; however, it remains unclear how these relate to motor neuron degeneration. Using a Drosophila model of TDP-43 proteinopathy that recapitulates several features of ALS including cytoplasmic inclusions, locomotor dysfunction, and reduced lifespan, we recently identified broad ranging metabolic deficits. Among these, glycolysis was found to be upregulated and genetic interaction experiments provided evidence for a compensatory neuroprotective mechanism. Indeed, despite upregulation of phosphofructokinase, the rate limiting enzyme in glycolysis, an increase in glycolysis using dietary and genetic manipulations was shown to mitigate locomotor dysfunction and increased lifespan in fly models of TDP-43 proteinopathy. To further investigate the effect on TDP-43 proteinopathy on glycolytic flux in motor neurons, a previously reported genetically encoded, FRET-based sensor, FLII12Pglu-700µδ6, was used. This sensor is comprised of a bacterial glucose-sensing domain and cyan and yellow fluorescent proteins as the FRET pair. Upon glucose binding, the sensor undergoes a conformational change allowing FRET to occur. Using FLII12Pglu-700µδ6, glucose uptake was found to be significantly increased in motor neurons expressing TDP-43
    MeSH term(s) Amyotrophic Lateral Sclerosis/genetics ; Animals ; Disease Models, Animal ; Drosophila ; Glucose ; TDP-43 Proteinopathies
    Chemical Substances Glucose (IY9XDZ35W2)
    Language English
    Publishing date 2021-08-03
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Video-Audio Media
    ZDB-ID 2259946-0
    ISSN 1940-087X ; 1940-087X
    ISSN (online) 1940-087X
    ISSN 1940-087X
    DOI 10.3791/62936
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: A Helping Hand: RNA-Binding Proteins Guide Gene-Binding Choices by Cohesin Complexes.

    Coyne, Alyssa N / Zarnescu, Daniela C

    PLoS genetics

    2016  Volume 12, Issue 11, Page(s) e1006419

    MeSH term(s) Cell Cycle Proteins/genetics ; Chromatids ; Chromosomal Proteins, Non-Histone/genetics ; DNA-Binding Proteins ; Drosophila/genetics ; RNA-Binding Proteins ; Response Elements ; Cohesins
    Chemical Substances Cell Cycle Proteins ; Chromosomal Proteins, Non-Histone ; DNA-Binding Proteins ; RNA-Binding Proteins
    Language English
    Publishing date 2016-11-17
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Comment
    ZDB-ID 2186725-2
    ISSN 1553-7404 ; 1553-7390
    ISSN (online) 1553-7404
    ISSN 1553-7390
    DOI 10.1371/journal.pgen.1006419
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article: TDP-43 Proteinopathy Causes Broad Metabolic Alterations including TCA Cycle Intermediates and Dopamine Levels in Drosophila Models of ALS.

    Loganathan, Suvithanandhini / Wilson, Bryce A / Carey, Sara B / Manzo, Ernesto / Joardar, Archi / Ugur, Berrak / Zarnescu, Daniela C

    Metabolites

    2022  Volume 12, Issue 2

    Abstract: Amyotrophic lateral sclerosis (ALS) is a fatal, complex neurodegenerative disorder that causes selective degeneration of motor neurons. ALS patients exhibit symptoms consistent with altered cellular energetics such as hypermetabolism, weight loss, ... ...

    Abstract Amyotrophic lateral sclerosis (ALS) is a fatal, complex neurodegenerative disorder that causes selective degeneration of motor neurons. ALS patients exhibit symptoms consistent with altered cellular energetics such as hypermetabolism, weight loss, dyslipidemia, insulin resistance, and altered glucose tolerance. Although evidence supports metabolic changes in ALS patients, metabolic alterations at a cellular level remain poorly understood. Here, we used a
    Language English
    Publishing date 2022-01-21
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2662251-8
    ISSN 2218-1989
    ISSN 2218-1989
    DOI 10.3390/metabo12020101
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article: To Be or Not To Be…Toxic-Is RNA Association With TDP-43 Complexes Deleterious or Protective in Neurodegeneration?

    Loganathan, Suvithanandhini / Lehmkuhl, Erik M / Eck, Randall J / Zarnescu, Daniela C

    Frontiers in molecular biosciences

    2020  Volume 6, Page(s) 154

    Abstract: TAR DNA binding protein (TDP-43) is a nucleic acid binding protein associated with insoluble cytoplasmic aggregates in several neurodegenerative disorders, including 97% of the ALS cases. In healthy individuals, TDP-43 is primarily localized to the ... ...

    Abstract TAR DNA binding protein (TDP-43) is a nucleic acid binding protein associated with insoluble cytoplasmic aggregates in several neurodegenerative disorders, including 97% of the ALS cases. In healthy individuals, TDP-43 is primarily localized to the nucleus; it can shuttle between the nucleus and the cytoplasm, and is involved in several aspects of RNA processing including transcription, splicing, RNA stability, transport, localization, stress granule (SG) formation, and translation. Upon stress, TDP-43 aggregates in the cytoplasm and associates with several types of RNA and protein assemblies, resulting in nuclear depletion of TDP-43. Under conditions of prolonged stress, cytoplasmic TDP-43 undergoes liquid-liquid phase separation (LLPS) and becomes less mobile. Evidence exists to support a scenario in which insoluble TDP-43 complexes sequester RNA and/or proteins causing disturbances in both ribostasis and proteostasis, which in turn contribute to neurodegeneration. However, the relationship between RNA binding and TDP-43 toxicity remains unclear. Recent studies provide conflicting views on the role of RNA in TDP-43 toxicity, with some finding RNA as a toxic factor whereby RNA binding contributes to TDP-43 toxicity, while others find RNA to be a protective factor that inhibits TDP-43 aggregation. Here we review and discuss these recent reports, which ultimately highlight the importance of understanding the heterogeneity of TDP-43 assemblies and collectively point to solubilizing TDP-43 as a potential therapeutic strategy.
    Language English
    Publishing date 2020-01-10
    Publishing country Switzerland
    Document type Journal Article ; Review
    ZDB-ID 2814330-9
    ISSN 2296-889X
    ISSN 2296-889X
    DOI 10.3389/fmolb.2019.00154
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  8. Article ; Online: -2019 PLOS Genetics Research Prize: Fruit fly school - language and dialects for communicating a threat.

    Barsh, Gregory S / Copenhaver, Gregory P / Prakash, Elapulli Sankaranarayanan / Zarnescu, Daniela C

    PLoS genetics

    2019  Volume 15, Issue 9, Page(s) e1008381

    MeSH term(s) Animals ; Awards and Prizes ; Drosophila/genetics ; Genetics ; Learning/physiology ; Models, Animal ; Research/trends ; Research Design/trends
    Language English
    Publishing date 2019-09-12
    Publishing country United States
    Document type Editorial ; Research Support, N.I.H., Extramural
    ZDB-ID 2186725-2
    ISSN 1553-7404 ; 1553-7390
    ISSN (online) 1553-7404
    ISSN 1553-7390
    DOI 10.1371/journal.pgen.1008381
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  9. Article ; Online: Dynamic duo - FMRP and TDP-43: Regulating common targets, causing different diseases.

    Ferro, Diana / Yao, Stephen / Zarnescu, Daniela C

    Brain research

    2018  Volume 1693, Issue Pt A, Page(s) 37–42

    Abstract: RNA binding proteins play essential roles during development and aging, and are also involved in disease pathomechanisms. RNA sequencing and omics analyses have provided a window into systems level alterations in neurological disease, and have identified ...

    Abstract RNA binding proteins play essential roles during development and aging, and are also involved in disease pathomechanisms. RNA sequencing and omics analyses have provided a window into systems level alterations in neurological disease, and have identified RNA processing defects among notable disease mechanisms. This review focuses on two seemingly distinct neurological disorders, the RNA binding proteins they are linked to, and their newly discovered functional relationship. When deficient, Fragile X Mental Retardation Protein (FMRP) causes developmental deficits and autistic behaviors while TAR-DNA Binding Protein (TDP-43) dysregulation causes age dependent neuronal degeneration. Recent findings that FMRP and TDP-43 associate in ribonuclear protein particles and share mRNA targets in neurons highlight the critical importance of translation regulation in synaptic plasticity and provide new perspectives on neuronal vulnerability during lifespan.
    MeSH term(s) Animals ; DNA-Binding Proteins/genetics ; DNA-Binding Proteins/metabolism ; DNA-Binding Proteins/physiology ; Disease Models, Animal ; Fragile X Mental Retardation Protein/genetics ; Fragile X Mental Retardation Protein/physiology ; Fragile X Syndrome/genetics ; Fragile X Syndrome/physiopathology ; Humans ; Neuronal Plasticity/physiology ; Neurons/metabolism ; Protein Biosynthesis/genetics ; Protein Biosynthesis/physiology ; RNA, Messenger/metabolism ; Receptors, Metabotropic Glutamate/physiology ; Ribonucleoproteins/metabolism ; Signal Transduction
    Chemical Substances DNA-Binding Proteins ; FMR1 protein, human ; RNA, Messenger ; Receptors, Metabotropic Glutamate ; Ribonucleoproteins ; TARDBP protein, human ; metabotropic glutamate receptor type 1 ; Fragile X Mental Retardation Protein (139135-51-6)
    Language English
    Publishing date 2018-04-30
    Publishing country Netherlands
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 1200-2
    ISSN 1872-6240 ; 0006-8993
    ISSN (online) 1872-6240
    ISSN 0006-8993
    DOI 10.1016/j.brainres.2018.04.034
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

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  10. Article: Failure to Deliver and Translate-New Insights into RNA Dysregulation in ALS.

    Coyne, Alyssa N / Zaepfel, Benjamin L / Zarnescu, Daniela C

    Frontiers in cellular neuroscience

    2017  Volume 11, Page(s) 243

    Abstract: Amyotrophic Lateral Sclerosis (ALS) is a progressive and fatal neurodegenerative disease affecting both upper and lower motor neurons. The molecular mechanisms underlying disease pathogenesis remain largely unknown. Multiple genetic loci including genes ... ...

    Abstract Amyotrophic Lateral Sclerosis (ALS) is a progressive and fatal neurodegenerative disease affecting both upper and lower motor neurons. The molecular mechanisms underlying disease pathogenesis remain largely unknown. Multiple genetic loci including genes involved in proteostasis and ribostasis have been linked to ALS providing key insights into the molecular mechanisms underlying disease. In particular, the identification of the RNA binding proteins TDP-43 and fused in sarcoma (FUS) as causative factors of ALS resulted in a paradigm shift centered on the study of RNA dysregulation as a major mechanism of disease. With wild-type TDP-43 pathology being found in ~97% of ALS cases and the identification of disease causing mutations within its sequence, TDP-43 has emerged as a prominent player in ALS. More recently, studies of the newly discovered
    Language English
    Publishing date 2017-08-17
    Publishing country Switzerland
    Document type Journal Article ; Review
    ZDB-ID 2452963-1
    ISSN 1662-5102
    ISSN 1662-5102
    DOI 10.3389/fncel.2017.00243
    Database MEDical Literature Analysis and Retrieval System OnLINE

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