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  1. Article ; Online: Author Correction: O-GlcNAc forces an α-synuclein amyloid strain with notably diminished seeding and pathology.

    Balana, Aaron T / Mahul-Mellier, Anne-Laure / Nguyen, Binh A / Horvath, Mian / Javed, Afraah / Hard, Eldon R / Jasiqi, Yllza / Singh, Preeti / Afrin, Shumaila / Pedretti, Rose / Singh, Virender / Lee, Virginia M-Y / Luk, Kelvin C / Saelices, Lorena / Lashuel, Hilal A / Pratt, Matthew R

    Nature chemical biology

    2024  Volume 20, Issue 5, Page(s) 656

    Language English
    Publishing date 2024-02-27
    Publishing country United States
    Document type Published Erratum
    ZDB-ID 2202962-X
    ISSN 1552-4469 ; 1552-4450
    ISSN (online) 1552-4469
    ISSN 1552-4450
    DOI 10.1038/s41589-024-01587-4
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 6251: Show issues Location:
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  2. Article ; Online: O-GlcNAc forces an α-synuclein amyloid strain with notably diminished seeding and pathology.

    Balana, Aaron T / Mahul-Mellier, Anne-Laure / Nguyen, Binh A / Horvath, Mian / Javed, Afraah / Hard, Eldon R / Jasiqi, Yllza / Singh, Preeti / Afrin, Shumaila / Pedretti, Rose / Singh, Virender / Lee, Virginia M-Y / Luk, Kelvin C / Saelices, Lorena / Lashuel, Hilal A / Pratt, Matthew R

    Nature chemical biology

    2024  Volume 20, Issue 5, Page(s) 646–655

    Abstract: Amyloid-forming proteins such α-synuclein and tau, which are implicated in Alzheimer's and Parkinson's disease, can form different fibril structures or strains with distinct toxic properties, seeding activities and pathology. Understanding the ... ...

    Abstract Amyloid-forming proteins such α-synuclein and tau, which are implicated in Alzheimer's and Parkinson's disease, can form different fibril structures or strains with distinct toxic properties, seeding activities and pathology. Understanding the determinants contributing to the formation of different amyloid features could open new avenues for developing disease-specific diagnostics and therapies. Here we report that O-GlcNAc modification of α-synuclein monomers results in the formation of amyloid fibril with distinct core structure, as revealed by cryogenic electron microscopy, and diminished seeding activity in seeding-based neuronal and rodent models of Parkinson's disease. Although the mechanisms underpinning the seeding neutralization activity of the O-GlcNAc-modified fibrils remain unclear, our in vitro mechanistic studies indicate that heat shock proteins interactions with O-GlcNAc fibril inhibit their seeding activity, suggesting that the O-GlcNAc modification may alter the interactome of the α-synuclein fibrils in ways that lead to reduce seeding activity in vivo. Our results show that posttranslational modifications, such as O-GlcNAc modification, of α-synuclein are key determinants of α-synuclein amyloid strains and pathogenicity.
    MeSH term(s) alpha-Synuclein/metabolism ; alpha-Synuclein/chemistry ; Amyloid/metabolism ; Humans ; Animals ; Mice ; Parkinson Disease/metabolism ; Parkinson Disease/pathology ; Acetylglucosamine/metabolism ; Acetylglucosamine/chemistry ; Protein Processing, Post-Translational ; Cryoelectron Microscopy ; Neurons/metabolism ; Neurons/pathology
    Chemical Substances alpha-Synuclein ; Amyloid ; Acetylglucosamine (V956696549)
    Language English
    Publishing date 2024-02-12
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
    ZDB-ID 2202962-X
    ISSN 1552-4469 ; 1552-4450
    ISSN (online) 1552-4469
    ISSN 1552-4450
    DOI 10.1038/s41589-024-01551-2
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 6251: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular
    ab Jg. 2022: Lesesaal (EG)
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  3. Article: High-Throughput Bioprinting of the Nasal Epithelium using Patient-derived Nasal Epithelial Cells.

    Derman, I Deniz / Yeo, Miji / Castaneda, Diana Cadena / Callender, Megan / Horvath, Mian / Mo, Zengshuo / Xiong, Ruoyun / Fleming, Elizabeth / Chen, Phylip / Peeples, Mark E / Palucka, Karolina / Oh, Julia / Ozbolat, Ibrahim T

    bioRxiv : the preprint server for biology

    2023  

    Abstract: Human nasal epithelial cells (hNECs) are an essential cell source for the reconstruction of the respiratory pseudostratified columnar epithelium composed of multiple cell types in the context of infection studies and disease modeling. Hitherto, manual ... ...

    Abstract Human nasal epithelial cells (hNECs) are an essential cell source for the reconstruction of the respiratory pseudostratified columnar epithelium composed of multiple cell types in the context of infection studies and disease modeling. Hitherto, manual seeding has been the dominant method for creating nasal epithelial tissue models. However, the manual approach is slow, low-throughput and has limitations in terms of achieving the intricate 3D structure of the natural nasal epithelium in a uniform manner. 3D Bioprinting has been utilized to reconstruct various epithelial tissue models, such as cutaneous, intestinal, alveolar, and bronchial epithelium, but there has been no attempt to use of 3D bioprinting technologies for reconstruction of the nasal epithelium. In this study, for the first time, we demonstrate the reconstruction of the nasal epithelium with the use of primary hNECs deposited on Transwell inserts via droplet-based bioprinting (DBB), which enabled high-throughput fabrication of the nasal epithelium in Transwell inserts of 24-well plates. DBB of nasal progenitor cells ranging from one-tenth to one-half of the cell seeding density employed during the conventional cell seeding approach enabled a high degree of differentiation with the presence of cilia and tight-junctions over a 4-week air-liquid interface culture. Single cell RNA sequencing of these cultures identified five major epithelial cells populations, including basal, suprabasal, goblet, club, and ciliated cells. These cultures recapitulated the pseudostratified columnar epithelial architecture present in the native nasal epithelium and were permissive to respiratory virus infection. These results denote the potential of 3D bioprinting for high-throughput fabrication of nasal epithelial tissue models not only for infection studies but also for other purposes such as disease modeling, immunological studies, and drug screening.
    Language English
    Publishing date 2023-03-30
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2023.03.29.534723
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: High-throughput bioprinting of the nasal epithelium using patient-derived nasal epithelial cells.

    Deniz Derman, I / Yeo, Miji / Castaneda, Diana Cadena / Callender, Megan / Horvath, Mian / Mo, Zengshuo / Xiong, Ruoyun / Fleming, Elizabeth / Chen, Phylip / Peeples, Mark E / Palucka, Karolina / Oh, Julia / Ozbolat, Ibrahim T

    Biofabrication

    2023  Volume 15, Issue 4

    Abstract: Progenitor human nasal epithelial cells (hNECs) are an essential cell source for the reconstruction of the respiratory pseudostratified columnar epithelium composed of multiple cell types in the context of infection studies and disease modeling. Hitherto, ...

    Abstract Progenitor human nasal epithelial cells (hNECs) are an essential cell source for the reconstruction of the respiratory pseudostratified columnar epithelium composed of multiple cell types in the context of infection studies and disease modeling. Hitherto, manual seeding has been the dominant method for creating nasal epithelial tissue models through biofabrication. However, this approach has limitations in terms of achieving the intricate three-dimensional (3D) structure of the natural nasal epithelium. 3D bioprinting has been utilized to reconstruct various epithelial tissue models, such as cutaneous, intestinal, alveolar, and bronchial epithelium, but there has been no attempt to use of 3D bioprinting technologies for reconstruction of the nasal epithelium. In this study, for the first time, we demonstrate the reconstruction of the nasal epithelium with the use of primary hNECs deposited on Transwell inserts via droplet-based bioprinting (DBB), which enabled high-throughput fabrication of the nasal epithelium in Transwell inserts of 24-well plates. DBB of progenitor hNECs ranging from one-tenth to one-half of the cell seeding density employed during the conventional cell seeding approach enabled a high degree of differentiation with the presence of cilia and tight-junctions over a 4 weeks air-liquid interface culture. Single cell RNA sequencing of these cultures identified five major epithelial cells populations, including basal, suprabasal, goblet, club, and ciliated cells. These cultures recapitulated the pseudostratified columnar epithelial architecture present in the native nasal epithelium and were permissive to respiratory virus infection. These results denote the potential of 3D bioprinting for high-throughput fabrication of nasal epithelial tissue models not only for infection studies but also for other purposes, such as disease modeling, immunological studies, and drug screening.
    MeSH term(s) Humans ; Bioprinting ; Nasal Mucosa/metabolism ; Epithelial Cells ; Respiratory Mucosa/metabolism ; Cilia
    Language English
    Publishing date 2023-08-14
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
    ZDB-ID 2500944-8
    ISSN 1758-5090 ; 1758-5082
    ISSN (online) 1758-5090
    ISSN 1758-5082
    DOI 10.1088/1758-5090/aced23
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article: O-GlcNAc modification forces the formation of an α-Synuclein amyloid-strain with notably diminished seeding activity and pathology.

    Balana, Aaron T / Mahul-Mellier, Anne-Laure / Nguyen, Binh A / Horvath, Mian / Javed, Afraah / Hard, Eldon R / Jasiqi, Yllza / Singh, Preeti / Afrin, Shumaila / Pedretti, Rose / Singh, Virender / Lee, Virginia M-Y / Luk, Kelvin C / Saelices, Lorena / Lashuel, Hilal A / Pratt, Matthew R

    bioRxiv : the preprint server for biology

    2023  

    Abstract: The process of amyloid fibril formation remains one of the primary targets for developing diagnostics and treatments for several neurodegenerative diseases (NDDs). Amyloid-forming proteins such α-Synuclein and Tau, which are implicated in the ... ...

    Abstract The process of amyloid fibril formation remains one of the primary targets for developing diagnostics and treatments for several neurodegenerative diseases (NDDs). Amyloid-forming proteins such α-Synuclein and Tau, which are implicated in the pathogenesis of Alzheimer's and Parkinson's disease, can form different types of fibril structure, or strains, that exhibit distinct structures, toxic properties, seeding activities, and pathology spreading patterns in the brain. Therefore, understanding the molecular and structural determinants contributing to the formation of different amyloid strains or their distinct features could open new avenues for developing disease-specific diagnostics and therapies. In this work, we report that O-GlcNAc modification of α-Synuclein monomers results in the formation of amyloid fibril with distinct core structure, as revealed by Cryo-EM, and diminished seeding activity in seeding-based neuronal and rodent models of Parkinson's disease. Although the mechanisms underpinning the seeding neutralization activity of the O-GlcNAc modified fibrils remain unclear, our
    Language English
    Publishing date 2023-03-07
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2023.03.07.531573
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: Snca

    Caputo, Anna / Liang, Yuling / Raabe, Tobias D / Lo, Angela / Horvath, Mian / Zhang, Bin / Brown, Hannah J / Stieber, Anna / Luk, Kelvin C

    eNeuro

    2020  Volume 7, Issue 4

    Abstract: α-Synuclein (aSyn) participates in synaptic vesicle trafficking and synaptic transmission but its misfolding is also strongly implicated in Parkinson's disease (PD) and other neurodegenerative synucleinopathies in which misfolded aSyn accumulates in ... ...

    Abstract α-Synuclein (aSyn) participates in synaptic vesicle trafficking and synaptic transmission but its misfolding is also strongly implicated in Parkinson's disease (PD) and other neurodegenerative synucleinopathies in which misfolded aSyn accumulates in different regions of the central and peripheral nervous systems. Although increased aSyn expression levels or altered aggregation propensities likely underlie familial PD with
    MeSH term(s) Animals ; Brain/metabolism ; Disease Models, Animal ; Mice ; Parkinson Disease ; Synapses/metabolism ; alpha-Synuclein/genetics ; alpha-Synuclein/metabolism
    Chemical Substances Snca protein, mouse ; alpha-Synuclein
    Language English
    Publishing date 2020-08-27
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2800598-3
    ISSN 2373-2822 ; 2373-2822
    ISSN (online) 2373-2822
    ISSN 2373-2822
    DOI 10.1523/ENEURO.0007-20.2020
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article: Potent inhibitors of toxic alpha-synuclein identified via cellular time-resolved FRET biosensors.

    Braun, Anthony R / Liao, Elly E / Horvath, Mian / Kalra, Prakriti / Acosta, Karen / Young, Malaney C / Kochen, Noah Nathan / Lo, Chih Hung / Brown, Roland / Evans, Michael D / Pomerantz, William C K / Rhoades, Elizabeth / Luk, Kelvin / Cornea, Razvan L / Thomas, David D / Sachs, Jonathan N

    NPJ Parkinson's disease

    2021  Volume 7, Issue 1, Page(s) 52

    Abstract: We have developed a high-throughput drug discovery platform, measuring fluorescence resonance energy transfer (FRET) with fluorescent alpha-synuclein (αSN) biosensors, to detect spontaneous pre-fibrillar oligomers in living cells. Our two αSN FRET ... ...

    Abstract We have developed a high-throughput drug discovery platform, measuring fluorescence resonance energy transfer (FRET) with fluorescent alpha-synuclein (αSN) biosensors, to detect spontaneous pre-fibrillar oligomers in living cells. Our two αSN FRET biosensors provide complementary insight into αSN oligomerization and conformation in order to improve the success of drug discovery campaigns for the treatment of Parkinson's disease. We measure FRET by fluorescence lifetime, rather than traditional fluorescence intensity, providing a structural readout with greater resolution and precision. This facilitates identification of compounds that cause subtle but significant conformational changes in the ensemble of oligomeric states that are easily missed using intensity-based FRET. We screened a 1280-compound small-molecule library and identified 21 compounds that changed the lifetime by >5 SD. Two of these compounds have nanomolar potency in protecting SH-SY5Y cells from αSN-induced death, providing a nearly tenfold improvement over known inhibitors. We tested the efficacy of several compounds in a primary mouse neuron assay of αSN pathology (phosphorylation of mouse αSN pre-formed fibrils) and show rescue of pathology for two of them. These hits were further characterized with biophysical and biochemical assays to explore potential mechanisms of action. In vitro αSN oligomerization, single-molecule FRET, and protein-observed fluorine NMR experiments demonstrate that these compounds modulate αSN oligomers but not monomers. Subsequent aggregation assays further show that these compounds also deter or block αSN fibril assembly.
    Language English
    Publishing date 2021-06-28
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2819218-7
    ISSN 2373-8057
    ISSN 2373-8057
    DOI 10.1038/s41531-021-00195-6
    Database MEDical Literature Analysis and Retrieval System OnLINE

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