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  1. Article: Multidimensional analysis of cortical interneuron synaptic features reveals underlying synaptic heterogeneity.

    Dummer, Patrick D / Lee, Dylan I / Hossain, Sakib / Wang, Runsheng / Evard, Andre / Newman, Gabriel / Ho, Claire / Schneider-Mizell, Casey M / Menon, Vilas / Au, Edmund

    bioRxiv : the preprint server for biology

    2024  

    Abstract: Cortical interneurons represent a diverse set of neuronal subtypes characterized in part by their striking degree of synaptic specificity. However, little is known about the extent of synaptic diversity because of the lack of unbiased methods to extract ... ...

    Abstract Cortical interneurons represent a diverse set of neuronal subtypes characterized in part by their striking degree of synaptic specificity. However, little is known about the extent of synaptic diversity because of the lack of unbiased methods to extract synaptic features among interneuron subtypes. Here, we develop an approach to aggregate image features from fluorescent confocal images of interneuron synapses and their post-synaptic targets, in order to characterize the heterogeneity of synapses at fine scale. We started by training a model that recognizes pre- and post-synaptic compartments and then determines the target of each genetically-identified interneuron synapse in vitro and in vivo. Our model extracts hundreds of spatial and intensity features from each analyzed synapse, constructing a multidimensional data set, consisting of millions of synapses, which allowed us to perform an unsupervised analysis on this dataset, uncovering novel synaptic subgroups. The subgroups were spatially distributed in a highly structured manner that revealed the local underlying topology of the postsynaptic environment. Dendrite-targeting subgroups were clustered onto subdomains of the dendrite along the proximal to distal axis. Soma-targeting subgroups were enriched onto different postsynaptic cell types. We also find that the two main subclasses of interneurons, basket cells and somatostatin interneurons, utilize distinct strategies to enact inhibitory coverage. Thus, our analysis of multidimensional synaptic features establishes a conceptual framework for studying interneuron synaptic diversity.
    Language English
    Publishing date 2024-04-17
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2024.03.22.586340
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: APOL1 toxin, innate immunity, and kidney injury.

    Limou, Sophie / Dummer, Patrick D / Nelson, George W / Kopp, Jeffrey B / Winkler, Cheryl A

    Kidney international

    2015  Volume 88, Issue 1, Page(s) 28–34

    Abstract: The discovery that two common APOL1 alleles were strongly associated with nondiabetic kidney diseases in African descent populations led to hope for improved diagnosis and treatment. Unfortunately, we still do not have a clear understanding of the ... ...

    Abstract The discovery that two common APOL1 alleles were strongly associated with nondiabetic kidney diseases in African descent populations led to hope for improved diagnosis and treatment. Unfortunately, we still do not have a clear understanding of the biological function played by APOL1 in podocytes or other kidney cells, nor how the renal risk alleles initiate the development of nephropathies. Important clues for APOL1 function may be gleaned from the natural defense mechanism of APOL1 against trypanosome infections and from similar proteins (e.g., diphtheria toxin, mammalian Bcl-2 family members). This review provides an update on the biological functions for circulating (trypanosome resistance) and intracellular (emerging role for autophagy) APOL1. Further, we introduce a multimer model for APOL1 in kidney cells that reconciles the gain-of-function variants with the recessive inheritance pattern of APOL1 renal risk alleles.
    MeSH term(s) Acute Kidney Injury/genetics ; Acute Kidney Injury/metabolism ; Alleles ; Apolipoprotein L1 ; Apolipoproteins/genetics ; Apolipoproteins/immunology ; Apolipoproteins/metabolism ; Autophagy ; Humans ; Immunity, Innate ; Lipoproteins, HDL/genetics ; Lipoproteins, HDL/immunology ; Lipoproteins, HDL/metabolism ; Trypanosomiasis/immunology
    Chemical Substances APOL1 protein, human ; Apolipoprotein L1 ; Apolipoproteins ; Lipoproteins, HDL
    Language English
    Publishing date 2015-04-08
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, N.I.H., Intramural ; Review
    ZDB-ID 120573-0
    ISSN 1523-1755 ; 0085-2538
    ISSN (online) 1523-1755
    ISSN 0085-2538
    DOI 10.1038/ki.2015.109
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    Zs.A 797: Show issues Location:
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  3. Article ; Online: Non-canonical Wnt Signaling through Ryk Regulates the Generation of Somatostatin- and Parvalbumin-Expressing Cortical Interneurons.

    McKenzie, Melissa G / Cobbs, Lucy V / Dummer, Patrick D / Petros, Timothy J / Halford, Michael M / Stacker, Steven A / Zou, Yimin / Fishell, Gord J / Au, Edmund

    Neuron

    2019  Volume 103, Issue 5, Page(s) 853–864.e4

    Abstract: GABAergic interneurons have many important functions in cortical circuitry, a reflection of their cell diversity. The developmental origins of this diversity are poorly understood. Here, we identify rostral-caudal regionality in Wnt exposure within the ... ...

    Abstract GABAergic interneurons have many important functions in cortical circuitry, a reflection of their cell diversity. The developmental origins of this diversity are poorly understood. Here, we identify rostral-caudal regionality in Wnt exposure within the interneuron progenitor zone delineating the specification of the two main interneuron subclasses. Caudally situated medial ganglionic eminence (MGE) progenitors receive high levels of Wnt signaling and give rise to somatostatin (SST)-expressing cortical interneurons. By contrast, parvalbumin (PV)-expressing basket cells originate mostly from the rostral MGE, where Wnt signaling is attenuated. Interestingly, rather than canonical signaling through β-catenin, signaling via the non-canonical Wnt receptor Ryk regulates interneuron cell-fate specification in vivo and in vitro. Indeed, gain of function of Ryk intracellular domain signaling regulates SST and PV fate in a dose-dependent manner, suggesting that Ryk signaling acts in a graded fashion. These data reveal an important role for non-canonical Wnt-Ryk signaling in establishing the correct ratios of cortical interneuron subtypes.
    MeSH term(s) Animals ; Cerebral Cortex/cytology ; Cerebral Cortex/embryology ; Cerebral Cortex/metabolism ; GABAergic Neurons/cytology ; GABAergic Neurons/metabolism ; Interneurons/cytology ; Interneurons/metabolism ; Mice ; Mouse Embryonic Stem Cells ; Neural Stem Cells/cytology ; Neural Stem Cells/metabolism ; Neurogenesis/genetics ; Parvalbumins/metabolism ; Receptor Protein-Tyrosine Kinases/genetics ; Somatostatin/metabolism ; Wnt Proteins/metabolism ; Wnt Signaling Pathway
    Chemical Substances Parvalbumins ; Wnt Proteins ; Somatostatin (51110-01-1) ; Receptor Protein-Tyrosine Kinases (EC 2.7.10.1) ; Ryk protein, mouse (EC 2.7.10.1)
    Language English
    Publishing date 2019-06-27
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 808167-0
    ISSN 1097-4199 ; 0896-6273
    ISSN (online) 1097-4199
    ISSN 0896-6273
    DOI 10.1016/j.neuron.2019.06.003
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    Zs.A 2496: Show issues Location:
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    Zs.MG 92: Show issues

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  4. Article ; Online: APOL1 Kidney Disease Risk Variants: An Evolving Landscape.

    Dummer, Patrick D / Limou, Sophie / Rosenberg, Avi Z / Heymann, Jurgen / Nelson, George / Winkler, Cheryl A / Kopp, Jeffrey B

    Seminars in nephrology

    2015  Volume 35, Issue 3, Page(s) 222–236

    Abstract: Apolipoprotein L1 (APOL1) genetic variants account for much of the excess risk of chronic and end-stage kidney disease, which results in a significant global health disparity for persons of African ancestry. We estimate the lifetime risk of kidney ... ...

    Abstract Apolipoprotein L1 (APOL1) genetic variants account for much of the excess risk of chronic and end-stage kidney disease, which results in a significant global health disparity for persons of African ancestry. We estimate the lifetime risk of kidney disease in APOL1 dual-risk allele individuals to be at least 15%. Experimental evidence suggests a direct role of APOL1 in pore formation, cellular injury, and programmed cell death in renal injury. The APOL1 BH3 motif, often associated with cell death, is unlikely to play a role in APOL1-induced cytotoxicity because it is not conserved within the APOL family and is dispensable for cell death in vitro. We discuss two models for APOL1 trypanolytic activity: one involving lysosome permeabilization and another involving colloid-osmotic swelling of the cell body, as well as their relevance to human pathophysiology. Experimental evidence from human cell culture models suggests that both mechanisms may be operative. A systems biology approach whereby APOL1-associated perturbations in gene and protein expression in affected individuals are correlated with molecular pathways may be productive to elucidate APOL1 function in vivo.
    MeSH term(s) Apolipoprotein L1 ; Apolipoproteins/genetics ; Apolipoproteins/metabolism ; Genetic Predisposition to Disease ; Genotype ; Humans ; Kidney Diseases/genetics ; Kidney Diseases/metabolism ; Lipoproteins, HDL/genetics ; Lipoproteins, HDL/metabolism ; Risk Factors
    Chemical Substances APOL1 protein, human ; Apolipoprotein L1 ; Apolipoproteins ; Lipoproteins, HDL
    Language English
    Publishing date 2015-07-26
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, N.I.H., Intramural ; Review
    ZDB-ID 604652-6
    ISSN 1558-4488 ; 0270-9295
    ISSN (online) 1558-4488
    ISSN 0270-9295
    DOI 10.1016/j.semnephrol.2015.04.008
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    Se 784: Show issues Location:
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  5. Article ; Online: APOL1 risk allele RNA contributes to renal toxicity by activating protein kinase R.

    Okamoto, Koji / Rausch, Jason W / Wakashin, Hidefumi / Fu, Yulong / Chung, Joon-Yong / Dummer, Patrick D / Shin, Myung K / Chandra, Preeti / Suzuki, Kosuke / Shrivastav, Shashi / Rosenberg, Avi Z / Hewitt, Stephen M / Ray, Patricio E / Noiri, Eisei / Le Grice, Stuart F J / Hoek, Maarten / Han, Zhe / Winkler, Cheryl A / Kopp, Jeffrey B

    Communications biology

    2018  Volume 1, Page(s) 188

    Abstract: ... ...

    Abstract APOL1
    Language English
    Publishing date 2018-11-07
    Publishing country England
    Document type Journal Article
    ISSN 2399-3642
    ISSN (online) 2399-3642
    DOI 10.1038/s42003-018-0188-2
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  6. Article ; Online: Transgenic expression of human APOL1 risk variants in podocytes induces kidney disease in mice.

    Beckerman, Pazit / Bi-Karchin, Jing / Park, Ae Seo Deok / Qiu, Chengxiang / Dummer, Patrick D / Soomro, Irfana / Boustany-Kari, Carine M / Pullen, Steven S / Miner, Jeffrey H / Hu, Chien-An A / Rohacs, Tibor / Inoue, Kazunori / Ishibe, Shuta / Saleem, Moin A / Palmer, Matthew B / Cuervo, Ana Maria / Kopp, Jeffrey B / Susztak, Katalin

    Nature medicine

    2017  Volume 23, Issue 4, Page(s) 429–438

    Abstract: African Americans have a heightened risk of developing chronic and end-stage kidney disease, an association that is largely attributed to two common genetic variants, termed G1 and G2, in the APOL1 gene. Direct evidence demonstrating that these APOL1 ... ...

    Abstract African Americans have a heightened risk of developing chronic and end-stage kidney disease, an association that is largely attributed to two common genetic variants, termed G1 and G2, in the APOL1 gene. Direct evidence demonstrating that these APOL1 risk alleles are pathogenic is still lacking because the APOL1 gene is present in only some primates and humans; thus it has been challenging to demonstrate experimental proof of causality of these risk alleles for renal disease. Here we generated mice with podocyte-specific inducible expression of the APOL1 reference allele (termed G0) or each of the risk-conferring alleles (G1 or G2). We show that mice with podocyte-specific expression of either APOL1 risk allele, but not of the G0 allele, develop functional (albuminuria and azotemia), structural (foot-process effacement and glomerulosclerosis) and molecular (gene-expression) changes that closely resemble human kidney disease. Disease development was cell-type specific and likely reversible, and the severity correlated with the level of expression of the risk allele. We further found that expression of the risk-variant APOL1 alleles interferes with endosomal trafficking and blocks autophagic flux, which ultimately leads to inflammatory-mediated podocyte death and glomerular scarring. In summary, this is the first demonstration that the expression of APOL1 risk alleles is causal for altered podocyte function and glomerular disease in vivo.
    MeSH term(s) Albuminuria/genetics ; Alleles ; Animals ; Apolipoprotein L1 ; Apolipoproteins/genetics ; Autophagy/genetics ; Azotemia/genetics ; Blotting, Western ; Endocytosis/genetics ; Endosomes/metabolism ; Fluorescent Antibody Technique ; Genetic Predisposition to Disease ; Genetic Variation ; Glomerulosclerosis, Focal Segmental/genetics ; Glomerulosclerosis, Focal Segmental/pathology ; HEK293 Cells ; HeLa Cells ; Humans ; Immunohistochemistry ; In Situ Nick-End Labeling ; Kidney Glomerulus/metabolism ; Kidney Glomerulus/pathology ; Kidney Glomerulus/ultrastructure ; Lipoproteins, HDL/genetics ; Mice ; Mice, Transgenic ; Microscopy, Electron ; Podocytes/metabolism ; Podocytes/ultrastructure ; Renal Insufficiency, Chronic/genetics ; Renal Insufficiency, Chronic/pathology
    Chemical Substances APOL1 protein, human ; Apolipoprotein L1 ; Apolipoproteins ; Lipoproteins, HDL
    Language English
    Publishing date 2017-02-20
    Publishing country United States
    Document type Journal Article
    ZDB-ID 1220066-9
    ISSN 1546-170X ; 1078-8956
    ISSN (online) 1546-170X
    ISSN 1078-8956
    DOI 10.1038/nm.4287
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    Zs.A 4212: Show issues Location:
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    Zs.MG 39: Show issues

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