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  1. Article ; Online: TDP-43 shapeshifts to encipher FTD severity.

    Barbieri, Edward M / Shorter, James

    Nature neuroscience

    2018  Volume 22, Issue 1, Page(s) 3–5

    MeSH term(s) Brain ; DNA-Binding Proteins ; Disease Progression ; Frontotemporal Dementia ; Frontotemporal Lobar Degeneration ; Humans
    Chemical Substances DNA-Binding Proteins ; TARDBP protein, human
    Language English
    Publishing date 2018-12-17
    Publishing country United States
    Document type Journal Article ; Comment
    ZDB-ID 1420596-8
    ISSN 1546-1726 ; 1097-6256
    ISSN (online) 1546-1726
    ISSN 1097-6256
    DOI 10.1038/s41593-018-0299-6
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 4891: Show issues Location:
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    Jg. 1995 - 2021: Lesesall (2.OG)
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    Zs.MG 67: Show issues

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  2. Article ; Online: Sequestration of TDP-43

    Peinado, Juan R / Chaplot, Kriti / Jarvela, Timothy S / Barbieri, Edward M / Shorter, James / Lindberg, Iris

    ACS chemical neuroscience

    2022  Volume 13, Issue 11, Page(s) 1651–1665

    Abstract: As neurons age, protein homeostasis becomes less efficient, resulting in misfolding and aggregation. Chaperone proteins perform vital functions in the maintenance of cellular proteostasis, and chaperone-based therapies that promote sequestration of toxic ...

    Abstract As neurons age, protein homeostasis becomes less efficient, resulting in misfolding and aggregation. Chaperone proteins perform vital functions in the maintenance of cellular proteostasis, and chaperone-based therapies that promote sequestration of toxic aggregates may prove useful in blocking the development of neurodegenerative disease. We previously demonstrated that proSAAS, a small secreted neuronal protein, exhibits potent chaperone activity against protein aggregation in vitro and blocks the cytotoxic effects of amyloid and synuclein oligomers in cell culture systems. We now examine whether cytoplasmic expression of proSAAS results in interactions with protein aggregates in this cellular compartment. We report that expression of proSAAS within the cytoplasm generates dense, membraneless 2 μm proSAAS spheres which progressively fuse to form larger spheres, suggesting liquid droplet-like properties. ProSAAS spheres selectively accumulate a C-terminally truncated fluorescently tagged form of TDP-43, initiating its cellular redistribution; these TDP-43-containing spheres also exhibit dynamic fusion. Efficient encapsulation of TDP-43 into proSAAS spheres is driven by its C-terminal prion-like domain; spheres must be formed for sequestration to occur. Three proSAAS sequences, a predicted coiled-coil, a conserved region (residues 158-169), and the positively charged sequence 181-185, are all required for proSAAS to form spheres able to encapsulate TDP-43 aggregates. Substitution of lysines for arginines in the 181-185 sequence results in nuclear translocation of proSAAS and encapsulation of nuclear-localized TDP-43
    MeSH term(s) Amyotrophic Lateral Sclerosis/metabolism ; Cytoplasm/metabolism ; DNA-Binding Proteins/genetics ; DNA-Binding Proteins/metabolism ; Humans ; Molecular Chaperones/genetics ; Neurodegenerative Diseases ; Protein Aggregates
    Chemical Substances DNA-Binding Proteins ; Molecular Chaperones ; Protein Aggregates
    Language English
    Publishing date 2022-05-12
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ISSN 1948-7193
    ISSN (online) 1948-7193
    DOI 10.1021/acschemneuro.2c00156
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: CRISPR screen for protein inclusion formation uncovers a role for SRRD in the regulation of intermediate filament dynamics and aggresome assembly.

    Sweeney, Katelyn M / Chantarawong, Sapanna / Barbieri, Edward M / Cajka, Greg / Liu, Matthew / Spruce, Lynn / Fazelinia, Hossein / Portz, Bede / Copley, Katie / Lapidot, Tomer / Duhamel, Lauren / Greenwald, Phoebe / Saida, Naseeb / Shalgi, Reut / Shorter, James / Shalem, Ophir

    PLoS genetics

    2024  Volume 20, Issue 2, Page(s) e1011138

    Abstract: The presence of large protein inclusions is a hallmark of neurodegeneration, and yet the precise molecular factors that contribute to their formation remain poorly understood. Screens using aggregation-prone proteins have commonly relied on downstream ... ...

    Abstract The presence of large protein inclusions is a hallmark of neurodegeneration, and yet the precise molecular factors that contribute to their formation remain poorly understood. Screens using aggregation-prone proteins have commonly relied on downstream toxicity as a readout rather than the direct formation of aggregates. Here, we combined a genome-wide CRISPR knockout screen with Pulse Shape Analysis, a FACS-based method for inclusion detection, to identify direct modifiers of TDP-43 aggregation in human cells. Our screen revealed both canonical and novel proteostasis genes, and unearthed SRRD, a poorly characterized protein, as a top regulator of protein inclusion formation. APEX biotin labeling reveals that SRRD resides in proximity to proteins that are involved in the formation and breakage of disulfide bonds and to intermediate filaments, suggesting a role in regulation of the spatial dynamics of the intermediate filament network. Indeed, loss of SRRD results in aberrant intermediate filament fibrils and the impaired formation of aggresomes, including blunted vimentin cage structure, during proteotoxic stress. Interestingly, SRRD also localizes to aggresomes and unfolded proteins, and rescues proteotoxicity in yeast whereby its N-terminal low complexity domain is sufficient to induce this affect. Altogether this suggests an unanticipated and broad role for SRRD in cytoskeletal organization and cellular proteostasis.
    MeSH term(s) Humans ; Intermediate Filaments/genetics ; Intermediate Filaments/metabolism ; Clustered Regularly Interspaced Short Palindromic Repeats ; Cytoskeleton/genetics ; Inclusion Bodies/genetics ; Inclusion Bodies/metabolism
    Language English
    Publishing date 2024-02-05
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2186725-2
    ISSN 1553-7404 ; 1553-7390
    ISSN (online) 1553-7404
    ISSN 1553-7390
    DOI 10.1371/journal.pgen.1011138
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Tuning Hsp104 specificity to selectively detoxify α-synuclein.

    Mack, Korrie L / Kim, Hanna / Barbieri, Edward M / Lin, JiaBei / Braganza, Sylvanne / Jackrel, Meredith E / DeNizio, Jamie E / Yan, Xiaohui / Chuang, Edward / Tariq, Amber / Cupo, Ryan R / Castellano, Laura M / Caldwell, Kim A / Caldwell, Guy A / Shorter, James

    Molecular cell

    2023  Volume 83, Issue 18, Page(s) 3314–3332.e9

    Abstract: Hsp104 is an AAA+ protein disaggregase that solubilizes and reactivates proteins trapped in aggregated states. We have engineered potentiated Hsp104 variants to mitigate toxic misfolding of α-synuclein, TDP-43, and FUS implicated in fatal ... ...

    Abstract Hsp104 is an AAA+ protein disaggregase that solubilizes and reactivates proteins trapped in aggregated states. We have engineered potentiated Hsp104 variants to mitigate toxic misfolding of α-synuclein, TDP-43, and FUS implicated in fatal neurodegenerative disorders. Though potent disaggregases, these enhanced Hsp104 variants lack substrate specificity and can have unfavorable off-target effects. Here, to lessen off-target effects, we engineer substrate-specific Hsp104 variants. By altering Hsp104 pore loops that engage substrate, we disambiguate Hsp104 variants that selectively suppress α-synuclein toxicity but not TDP-43 or FUS toxicity. Remarkably, α-synuclein-specific Hsp104 variants emerge that mitigate α-synuclein toxicity via distinct ATPase-dependent mechanisms involving α-synuclein disaggregation or detoxification of soluble α-synuclein conformers. Importantly, both types of α-synuclein-specific Hsp104 variant reduce dopaminergic neurodegeneration in a C. elegans model of Parkinson's disease more effectively than non-specific variants. We suggest that increasing the substrate specificity of enhanced disaggregases could be applied broadly to tailor therapeutics for neurodegenerative disease.
    MeSH term(s) Animals ; Humans ; alpha-Synuclein/genetics ; Saccharomyces cerevisiae Proteins/metabolism ; Heat-Shock Proteins/genetics ; Heat-Shock Proteins/metabolism ; Neurodegenerative Diseases ; Caenorhabditis elegans/genetics ; Caenorhabditis elegans/metabolism
    Chemical Substances alpha-Synuclein ; Saccharomyces cerevisiae Proteins ; Heat-Shock Proteins
    Language English
    Publishing date 2023-08-24
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 1415236-8
    ISSN 1097-4164 ; 1097-2765
    ISSN (online) 1097-4164
    ISSN 1097-2765
    DOI 10.1016/j.molcel.2023.07.029
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 5055: Show issues Location:
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  5. Article ; Online: Precise Editing at DNA Replication Forks Enables Multiplex Genome Engineering in Eukaryotes.

    Barbieri, Edward M / Muir, Paul / Akhuetie-Oni, Benjamin O / Yellman, Christopher M / Isaacs, Farren J

    Cell

    2017  Volume 171, Issue 6, Page(s) 1453–1467.e13

    Abstract: We describe a multiplex genome engineering technology in Saccharomyces cerevisiae based on annealing synthetic oligonucleotides at the lagging strand of DNA replication. The mechanism is independent of Rad51-directed homologous recombination and avoids ... ...

    Abstract We describe a multiplex genome engineering technology in Saccharomyces cerevisiae based on annealing synthetic oligonucleotides at the lagging strand of DNA replication. The mechanism is independent of Rad51-directed homologous recombination and avoids the creation of double-strand DNA breaks, enabling precise chromosome modifications at single base-pair resolution with an efficiency of >40%, without unintended mutagenic changes at the targeted genetic loci. We observed the simultaneous incorporation of up to 12 oligonucleotides with as many as 60 targeted mutations in one transformation. Iterative transformations of a complex pool of oligonucleotides rapidly produced large combinatorial genomic diversity >10
    MeSH term(s) DNA Replication ; Escherichia coli/genetics ; Gene Editing ; Genetic Engineering/methods ; Oligonucleotides/chemistry ; Saccharomyces cerevisiae/genetics
    Chemical Substances Oligonucleotides
    Language English
    Publishing date 2017-11-16
    Publishing country United States
    Document type Journal Article
    ZDB-ID 187009-9
    ISSN 1097-4172 ; 0092-8674
    ISSN (online) 1097-4172
    ISSN 0092-8674
    DOI 10.1016/j.cell.2017.10.034
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