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  1. Article: Longitudinal modeling of human neuronal aging identifies RCAN1-TFEB pathway contributing to neurodegeneration of Huntington's disease.

    Lee, Seong Won / Oh, Young Mi / Victor, Matheus B / Strunilin, Ilya / Chen, Shawei / Dahiya, Sonika / Dolle, Roland E / Pak, Stephen C / Silverman, Gary A / Perlmutter, David H / Yoo, Andrew S

    Research square

    2023  

    Abstract: Aging is a common risk factor in neurodegenerative disorders and the ability to investigate aging of neurons in an isogenic background would facilitate discovering the interplay between neuronal aging and onset of neurodegeneration. Here, we perform ... ...

    Abstract Aging is a common risk factor in neurodegenerative disorders and the ability to investigate aging of neurons in an isogenic background would facilitate discovering the interplay between neuronal aging and onset of neurodegeneration. Here, we perform direct neuronal reprogramming of longitudinally collected human fibroblasts to reveal genetic pathways altered at different ages. Comparative transcriptome analysis of longitudinally aged striatal medium spiny neurons (MSNs), a primary neuronal subtype affected in Huntington's disease (HD), identified pathways associated with RCAN1, a negative regulator of calcineurin. Notably, RCAN1 undergoes age-dependent increase at the protein level detected in reprogrammed MSNs as well as in human postmortem striatum. In patient-derived MSNs of adult-onset HD (HD-MSNs), counteracting
    Language English
    Publishing date 2023-05-09
    Publishing country United States
    Document type Preprint
    DOI 10.21203/rs.3.rs-2815300/v1
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Longitudinal modeling of human neuronal aging reveals the contribution of the RCAN1-TFEB pathway to Huntington's disease neurodegeneration.

    Lee, Seong Won / Oh, Young Mi / Victor, Matheus B / Yang, Yan / Chen, Shawei / Strunilin, Ilya / Dahiya, Sonika / Dolle, Roland E / Pak, Stephen C / Silverman, Gary A / Perlmutter, David H / Yoo, Andrew S

    Nature aging

    2023  Volume 4, Issue 1, Page(s) 95–109

    Abstract: Aging is a common risk factor in neurodegenerative disorders. Investigating neuronal aging in an isogenic background stands to facilitate analysis of the interplay between neuronal aging and neurodegeneration. Here we perform direct neuronal ... ...

    Abstract Aging is a common risk factor in neurodegenerative disorders. Investigating neuronal aging in an isogenic background stands to facilitate analysis of the interplay between neuronal aging and neurodegeneration. Here we perform direct neuronal reprogramming of longitudinally collected human fibroblasts to reveal genetic pathways altered at different ages. Comparative transcriptome analysis of longitudinally aged striatal medium spiny neurons (MSNs) in Huntington's disease identified pathways involving RCAN1, a negative regulator of calcineurin. Notably, RCAN1 protein increased with age in reprogrammed MSNs as well as in human postmortem striatum and RCAN1 knockdown rescued patient-derived MSNs of Huntington's disease from degeneration. RCAN1 knockdown enhanced chromatin accessibility of genes involved in longevity and autophagy, mediated through enhanced calcineurin activity, leading to TFEB's nuclear localization by dephosphorylation. Furthermore, G2-115, an analog of glibenclamide with autophagy-enhancing activities, reduced the RCAN1-calcineurin interaction, phenocopying the effect of RCAN1 knockdown. Our results demonstrate that targeting RCAN1 genetically or pharmacologically can increase neuronal resilience in Huntington's disease.
    MeSH term(s) Humans ; Aged ; Calcineurin/genetics ; Huntington Disease/genetics ; Aging/genetics ; Transcription Factors/metabolism ; Corpus Striatum/metabolism ; DNA-Binding Proteins/metabolism ; Muscle Proteins/genetics ; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/metabolism
    Chemical Substances Calcineurin (EC 3.1.3.16) ; Transcription Factors ; RCAN1 protein, human ; DNA-Binding Proteins ; Muscle Proteins ; TFEB protein, human ; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
    Language English
    Publishing date 2023-12-08
    Publishing country United States
    Document type Journal Article
    ISSN 2662-8465
    ISSN (online) 2662-8465
    DOI 10.1038/s43587-023-00538-3
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Combinations of DIPs and Dprs control organization of olfactory receptor neuron terminals in Drosophila.

    Barish, Scott / Nuss, Sarah / Strunilin, Ilya / Bao, Suyang / Mukherjee, Sayan / Jones, Corbin D / Volkan, Pelin C

    PLoS genetics

    2018  Volume 14, Issue 8, Page(s) e1007560

    Abstract: In Drosophila, 50 classes of olfactory receptor neurons (ORNs) connect to 50 class-specific and uniquely positioned glomeruli in the antennal lobe. Despite the identification of cell surface receptors regulating axon guidance, how ORN axons sort to form ... ...

    Abstract In Drosophila, 50 classes of olfactory receptor neurons (ORNs) connect to 50 class-specific and uniquely positioned glomeruli in the antennal lobe. Despite the identification of cell surface receptors regulating axon guidance, how ORN axons sort to form 50 stereotypical glomeruli remains unclear. Here we show that the heterophilic cell adhesion proteins, DIPs and Dprs, are expressed in ORNs during glomerular formation. Many ORN classes express a unique combination of DIPs/dprs, with neurons of the same class expressing interacting partners, suggesting a role in class-specific self-adhesion between ORN axons. Analysis of DIP/Dpr expression revealed that ORNs that target neighboring glomeruli have different combinations, and ORNs with very similar DIP/Dpr combinations can project to distant glomeruli in the antennal lobe. DIP/Dpr profiles are dynamic during development and correlate with sensilla type lineage for some ORN classes. Perturbations of DIP/dpr gene function result in local projection defects of ORN axons and glomerular positioning, without altering correct matching of ORNs with their target neurons. Our results suggest that context-dependent differential adhesion through DIP/Dpr combinations regulate self-adhesion and sort ORN axons into uniquely positioned glomeruli.
    MeSH term(s) Animals ; Axons/physiology ; Cell Adhesion ; Drosophila/genetics ; Drosophila/physiology ; Drosophila Proteins/genetics ; Drosophila Proteins/physiology ; Gene Expression Regulation ; Genotyping Techniques ; Models, Theoretical ; Olfactory Pathways/physiology ; Olfactory Receptor Neurons/physiology ; Sequence Analysis, RNA
    Chemical Substances Drosophila Proteins
    Language English
    Publishing date 2018-08-13
    Publishing country United States
    Document type Journal Article ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 2186725-2
    ISSN 1553-7404 ; 1553-7390
    ISSN (online) 1553-7404
    ISSN 1553-7390
    DOI 10.1371/journal.pgen.1007560
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Epigenetic and transcriptomic characterization reveals progression markers and essential pathways in clear cell renal cell carcinoma.

    Wu, Yige / Terekhanova, Nadezhda V / Caravan, Wagma / Naser Al Deen, Nataly / Lal, Preet / Chen, Siqi / Mo, Chia-Kuei / Cao, Song / Li, Yize / Karpova, Alla / Liu, Ruiyang / Zhao, Yanyan / Shinkle, Andrew / Strunilin, Ilya / Weimholt, Cody / Sato, Kazuhito / Yao, Lijun / Serasanambati, Mamatha / Yang, Xiaolu /
    Wyczalkowski, Matthew / Zhu, Houxiang / Zhou, Daniel Cui / Jayasinghe, Reyka G / Mendez, Daniel / Wendl, Michael C / Clark, David / Newton, Chelsea / Ruan, Yijun / Reimers, Melissa A / Pachynski, Russell K / Kinsinger, Chris / Jewell, Scott / Chan, Daniel W / Zhang, Hui / Chaudhuri, Aadel A / Chheda, Milan G / Humphreys, Benjamin D / Mesri, Mehdi / Rodriguez, Henry / Hsieh, James J / Ding, Li / Chen, Feng

    Nature communications

    2023  Volume 14, Issue 1, Page(s) 1681

    Abstract: Identifying tumor-cell-specific markers and elucidating their epigenetic regulation and spatial heterogeneity provides mechanistic insights into cancer etiology. Here, we perform snRNA-seq and snATAC-seq in 34 and 28 human clear cell renal cell carcinoma ...

    Abstract Identifying tumor-cell-specific markers and elucidating their epigenetic regulation and spatial heterogeneity provides mechanistic insights into cancer etiology. Here, we perform snRNA-seq and snATAC-seq in 34 and 28 human clear cell renal cell carcinoma (ccRCC) specimens, respectively, with matched bulk proteogenomics data. By identifying 20 tumor-specific markers through a multi-omics tiered approach, we reveal an association between higher ceruloplasmin (CP) expression and reduced survival. CP knockdown, combined with spatial transcriptomics, suggests a role for CP in regulating hyalinized stroma and tumor-stroma interactions in ccRCC. Intratumoral heterogeneity analysis portrays tumor cell-intrinsic inflammation and epithelial-mesenchymal transition (EMT) as two distinguishing features of tumor subpopulations. Finally, BAP1 mutations are associated with widespread reduction of chromatin accessibility, while PBRM1 mutations generally increase accessibility, with the former affecting five times more accessible peaks than the latter. These integrated analyses reveal the cellular architecture of ccRCC, providing insights into key markers and pathways in ccRCC tumorigenesis.
    MeSH term(s) Humans ; Carcinoma, Renal Cell/pathology ; Kidney Neoplasms/pathology ; Transcriptome ; Epigenesis, Genetic ; Tumor Suppressor Proteins/genetics ; Gene Expression Regulation, Neoplastic
    Chemical Substances Tumor Suppressor Proteins
    Language English
    Publishing date 2023-03-27
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2553671-0
    ISSN 2041-1723 ; 2041-1723
    ISSN (online) 2041-1723
    ISSN 2041-1723
    DOI 10.1038/s41467-023-37211-7
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Author Correction: Epigenetic and transcriptomic characterization reveals progression markers and essential pathways in clear cell renal cell carcinoma.

    Wu, Yige / Terekhanova, Nadezhda V / Caravan, Wagma / Naser Al Deen, Nataly / Lal, Preet / Chen, Siqi / Mo, Chia-Kuei / Cao, Song / Li, Yize / Karpova, Alla / Liu, Ruiyang / Zhao, Yanyan / Shinkle, Andrew / Strunilin, Ilya / Weimholt, Cody / Sato, Kazuhito / Yao, Lijun / Serasanambati, Mamatha / Yang, Xiaolu /
    Wyczalkowski, Matthew / Zhu, Houxiang / Zhou, Daniel Cui / Jayasinghe, Reyka G / Mendez, Daniel / Wendl, Michael C / Clark, David / Newton, Chelsea / Ruan, Yijun / Reimers, Melissa A / Pachynski, Russell K / Kinsinger, Chris / Jewell, Scott / Chan, Daniel W / Zhang, Hui / Chaudhuri, Aadel A / Chheda, Milan G / Humphreys, Benjamin D / Mesri, Mehdi / Rodriguez, Henry / Hsieh, James J / Ding, Li / Chen, Feng

    Nature communications

    2023  Volume 14, Issue 1, Page(s) 2817

    Language English
    Publishing date 2023-05-17
    Publishing country England
    Document type Published Erratum
    ZDB-ID 2553671-0
    ISSN 2041-1723 ; 2041-1723
    ISSN (online) 2041-1723
    ISSN 2041-1723
    DOI 10.1038/s41467-023-38561-y
    Database MEDical Literature Analysis and Retrieval System OnLINE

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