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  1. Article ; Online: Loss of the Vitamin B-12 Transport Protein Tcn2 Results in Maternally Inherited Growth and Developmental Defects in Zebrafish.

    Benoit, Courtney R / Walsh, Darren J / Mekerishvili, Levan / Houerbi, Nadia / Stanton, Abigail E / McGaughey, David M / Brody, Lawrence C

    The Journal of nutrition

    2021  Volume 151, Issue 9, Page(s) 2522–2532

    Abstract: Background: In humans, vitamin B-12 (cobalamin) transport involves 3 paralogous proteins: transcobalamin, haptocorrin, and intrinsic factor. Zebrafish (Danio rerio) express 3 genes that encode proteins homologous to known B-12 carrier proteins: tcn2 (a ... ...

    Abstract Background: In humans, vitamin B-12 (cobalamin) transport involves 3 paralogous proteins: transcobalamin, haptocorrin, and intrinsic factor. Zebrafish (Danio rerio) express 3 genes that encode proteins homologous to known B-12 carrier proteins: tcn2 (a transcobalamin ortholog) and 2 atypical β-domain-only homologs, tcnba and tcnbb.
    Objectives: Given the orthologous relation between zebrafish Tcn2 and human transcobalamin, we hypothesized that zebrafish carrying null mutations of tcn2 would exhibit phenotypes consistent with vitamin B-12 deficiency.
    Methods: First-generation and second-generation tcn2-/- zebrafish were characterized using phenotypic assessments, metabolic analyses, viability studies, and transcriptomics.
    Results: Homozygous tcn2-/- fish produced from a heterozygous cross are viable and fertile but exhibit reduced growth, which persists into adulthood. When first-generation female tcn2-/- fish are bred, their offspring exhibit gross developmental and metabolic defects. These phenotypes are observed in all offspring from a tcn2-/- female regardless of the genotype of the male mating partner, suggesting a maternal effect, and can be rescued with vitamin B-12 supplementation. Transcriptome analyses indicate that offspring from a tcn2-/- female exhibit expression profiles distinct from those of offspring from a tcn2+/+ female, which demonstrate dysregulation of visual perception, fatty acid metabolism, and neurotransmitter signaling pathways.
    Conclusions: Our findings suggest that the deposition of vitamin B-12 in the yolk by tcn2-/- females may be insufficient to support the early development of their offspring. These data present a compelling model to study the effects of vitamin B-12 deficiency on early development, with a particular emphasis on transgenerational effects and gene-environment interactions.
    MeSH term(s) Adult ; Animals ; Female ; Humans ; Male ; Maternal Inheritance ; Transcobalamins/genetics ; Vitamin B 12 ; Vitamins ; Zebrafish/genetics
    Chemical Substances Transcobalamins ; Vitamins ; Vitamin B 12 (P6YC3EG204)
    Language English
    Publishing date 2021-06-18
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Intramural
    ZDB-ID 218373-0
    ISSN 1541-6100 ; 0022-3166
    ISSN (online) 1541-6100
    ISSN 0022-3166
    DOI 10.1093/jn/nxab151
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: INPP5D regulates inflammasome activation in human microglia.

    Chou, Vicky / Pearse, Richard V / Aylward, Aimee J / Ashour, Nancy / Taga, Mariko / Terzioglu, Gizem / Fujita, Masashi / Fancher, Seeley B / Sigalov, Alina / Benoit, Courtney R / Lee, Hyo / Lam, Matti / Seyfried, Nicholas T / Bennett, David A / De Jager, Philip L / Menon, Vilas / Young-Pearse, Tracy L

    Nature communications

    2023  Volume 14, Issue 1, Page(s) 7552

    Abstract: Microglia and neuroinflammation play an important role in the development and progression of Alzheimer's disease (AD). Inositol polyphosphate-5-phosphatase D (INPP5D/SHIP1) is a myeloid-expressed gene genetically-associated with AD. Through unbiased ... ...

    Abstract Microglia and neuroinflammation play an important role in the development and progression of Alzheimer's disease (AD). Inositol polyphosphate-5-phosphatase D (INPP5D/SHIP1) is a myeloid-expressed gene genetically-associated with AD. Through unbiased analyses of RNA and protein profiles in INPP5D-disrupted iPSC-derived human microglia, we find that reduction in INPP5D activity is associated with molecular profiles consistent with disrupted autophagy and inflammasome activation. These findings are validated through targeted pharmacological experiments which demonstrate that reduced INPP5D activity induces the formation of the NLRP3 inflammasome, cleavage of CASP1, and secretion of IL-1β and IL-18. Further, in-depth analyses of human brain tissue across hundreds of individuals using a multi-analytic approach provides evidence that a reduction in function of INPP5D in microglia results in inflammasome activation in AD. These findings provide insights into the molecular mechanisms underlying microglia-mediated processes in AD and highlight the inflammasome as a potential therapeutic target for modulating INPP5D-mediated vulnerability to AD.
    MeSH term(s) Humans ; Inflammasomes/metabolism ; NLR Family, Pyrin Domain-Containing 3 Protein/genetics ; NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; Microglia/metabolism ; Alzheimer Disease/metabolism ; Brain/metabolism ; Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases/metabolism
    Chemical Substances Inflammasomes ; NLR Family, Pyrin Domain-Containing 3 Protein ; INPP5D protein, human (EC 3.1.3.86) ; Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases (EC 3.1.3.86)
    Language English
    Publishing date 2023-11-29
    Publishing country England
    Document type Journal Article
    ZDB-ID 2553671-0
    ISSN 2041-1723 ; 2041-1723
    ISSN (online) 2041-1723
    ISSN 2041-1723
    DOI 10.1038/s41467-023-42819-w
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article: Cell-type-specific regulation of APOE levels in human neurons by the Alzheimer's disease risk gene SORL1.

    Lee, Hyo / Aylward, Aimee J / Pearse, Richard V / Hsieh, Yi-Chen / Augur, Zachary M / Benoit, Courtney R / Chou, Vicky / Knupp, Allison / Pan, Cheryl / Goberdhan, Srilakshmi / Duong, Duc M / Seyfried, Nicholas T / Bennett, David A / Klein, Hans-Ulrich / De Jager, Philip L / Menon, Vilas / Young, Jessica E / Young-Pearse, Tracy L

    bioRxiv : the preprint server for biology

    2023  

    Abstract: SORL1 is strongly implicated in the pathogenesis of Alzheimer's disease (AD) through human genetic studies that point to an association of reduced SORL1 levels with higher risk for AD. To interrogate the role(s) of SORL1 in human brain cells, SORL1 null ... ...

    Abstract SORL1 is strongly implicated in the pathogenesis of Alzheimer's disease (AD) through human genetic studies that point to an association of reduced SORL1 levels with higher risk for AD. To interrogate the role(s) of SORL1 in human brain cells, SORL1 null iPSCs were generated, followed by differentiation to neuron, astrocyte, microglia, and endothelial cell fates. Loss of SORL1 led to alterations in both overlapping and distinct pathways across cell types, with the greatest effects in neurons and astrocytes. Intriguingly, SORL1 loss led to a dramatic neuron-specific reduction in APOE levels. Further, analyses of iPSCs derived from a human aging cohort revealed a neuron-specific linear correlation between SORL1 and APOE RNA and protein levels, a finding validated in human post-mortem brain. Pathway analysis implicated intracellular transport pathways and TGF- β/SMAD signaling in the function of SORL1 in neurons. In accord, enhancement of retromer-mediated trafficking and autophagy rescued elevated phospho-tau observed in SORL1 null neurons but did not rescue APOE levels, suggesting that these phenotypes are separable. Stimulation and inhibition of SMAD signaling modulated APOE RNA levels in a SORL1-dependent manner. These studies provide a mechanistic link between two of the strongest genetic risk factors for AD.
    Language English
    Publishing date 2023-02-25
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2023.02.25.530017
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Cell-type-specific regulation of APOE and CLU levels in human neurons by the Alzheimer's disease risk gene SORL1.

    Lee, Hyo / Aylward, Aimee J / Pearse, Richard V / Lish, Alexandra M / Hsieh, Yi-Chen / Augur, Zachary M / Benoit, Courtney R / Chou, Vicky / Knupp, Allison / Pan, Cheryl / Goberdhan, Srilakshmi / Duong, Duc M / Seyfried, Nicholas T / Bennett, David A / Taga, Mariko F / Huynh, Kevin / Arnold, Matthias / Meikle, Peter J / De Jager, Philip L /
    Menon, Vilas / Young, Jessica E / Young-Pearse, Tracy L

    Cell reports

    2023  Volume 42, Issue 8, Page(s) 112994

    Abstract: SORL1 is implicated in the pathogenesis of Alzheimer's disease (AD) through genetic studies. To interrogate the roles of SORL1 in human brain cells, SORL1-null induced pluripotent stem cells (iPSCs) were differentiated to neuron, astrocyte, microglial, ... ...

    Abstract SORL1 is implicated in the pathogenesis of Alzheimer's disease (AD) through genetic studies. To interrogate the roles of SORL1 in human brain cells, SORL1-null induced pluripotent stem cells (iPSCs) were differentiated to neuron, astrocyte, microglial, and endothelial cell fates. Loss of SORL1 leads to alterations in both overlapping and distinct pathways across cell types, with the greatest effects in neurons and astrocytes. SORL1 loss induces a neuron-specific reduction in apolipoprotein E (APOE) and clusterin (CLU) and altered lipid profiles. Analyses of iPSCs derived from a large cohort reveal a neuron-specific association between SORL1, APOE, and CLU levels, a finding validated in postmortem brain. Enhancement of retromer-mediated trafficking rescues tau phenotypes observed in SORL1-null neurons but does not rescue APOE levels. Pathway analyses implicate transforming growth factor β (TGF-β)/SMAD signaling in SORL1 function, and modulating SMAD signaling in neurons alters APOE RNA levels in a SORL1-dependent manner. Taken together, these data provide a mechanistic link between strong genetic risk factors for AD.
    MeSH term(s) Humans ; Clusterin/genetics ; Alzheimer Disease/genetics ; Neurons ; Cell Growth Processes ; Apolipoproteins E/genetics ; LDL-Receptor Related Proteins/genetics ; Membrane Transport Proteins
    Chemical Substances Clusterin ; Apolipoproteins E ; SORL1 protein, human ; LDL-Receptor Related Proteins ; Membrane Transport Proteins ; CLU protein, human
    Language English
    Publishing date 2023-08-22
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 2649101-1
    ISSN 2211-1247 ; 2211-1247
    ISSN (online) 2211-1247
    ISSN 2211-1247
    DOI 10.1016/j.celrep.2023.112994
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Functional and phylogenetic characterization of noncanonical vitamin B

    Benoit, Courtney R / Stanton, Abigail E / Tartanian, Aileen C / Motzer, Andrew R / McGaughey, David M / Bond, Stephen R / Brody, Lawrence C

    The Journal of biological chemistry

    2018  Volume 293, Issue 45, Page(s) 17606–17621

    Abstract: In humans, transport of food-derived cobalamin (vitamin ... ...

    Abstract In humans, transport of food-derived cobalamin (vitamin B
    MeSH term(s) Animals ; CRISPR-Cas Systems ; Protein Domains ; Transcobalamins/chemistry ; Transcobalamins/genetics ; Transcobalamins/metabolism ; Vitamin B 12/chemistry ; Vitamin B 12/genetics ; Vitamin B 12/metabolism ; Zebrafish/genetics ; Zebrafish/metabolism ; Zebrafish Proteins/chemistry ; Zebrafish Proteins/genetics ; Zebrafish Proteins/metabolism
    Chemical Substances Transcobalamins ; Zebrafish Proteins ; Vitamin B 12 (P6YC3EG204)
    Language English
    Publishing date 2018-09-20
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, N.I.H., Intramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2997-x
    ISSN 1083-351X ; 0021-9258
    ISSN (online) 1083-351X
    ISSN 0021-9258
    DOI 10.1074/jbc.RA118.005323
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: Stem cell-derived neurons reflect features of protein networks, neuropathology, and cognitive outcome of their aged human donors.

    Lagomarsino, Valentina N / Pearse, Richard V / Liu, Lei / Hsieh, Yi-Chen / Fernandez, Marty A / Vinton, Elizabeth A / Paull, Daniel / Felsky, Daniel / Tasaki, Shinya / Gaiteri, Chris / Vardarajan, Badri / Lee, Hyo / Muratore, Christina R / Benoit, Courtney R / Chou, Vicky / Fancher, Seeley B / He, Amy / Merchant, Julie P / Duong, Duc M /
    Martinez, Hector / Zhou, Monica / Bah, Fatmata / Vicent, Maria A / Stricker, Jonathan M S / Xu, Jishu / Dammer, Eric B / Levey, Allan I / Chibnik, Lori B / Menon, Vilas / Seyfried, Nicholas T / De Jager, Philip L / Noggle, Scott / Selkoe, Dennis J / Bennett, David A / Young-Pearse, Tracy L

    Neuron

    2021  Volume 109, Issue 21, Page(s) 3402–3420.e9

    Abstract: We have generated a controlled and manipulable resource that captures genetic risk for Alzheimer's disease: iPSC lines from 53 individuals coupled with RNA and proteomic profiling of both iPSC-derived neurons and brain tissue of the same individuals. ... ...

    Abstract We have generated a controlled and manipulable resource that captures genetic risk for Alzheimer's disease: iPSC lines from 53 individuals coupled with RNA and proteomic profiling of both iPSC-derived neurons and brain tissue of the same individuals. Data collected for each person include genome sequencing, longitudinal cognitive scores, and quantitative neuropathology. The utility of this resource is exemplified here by analyses of neurons derived from these lines, revealing significant associations between specific Aβ and tau species and the levels of plaque and tangle deposition in the brain and, more importantly, with the trajectory of cognitive decline. Proteins and networks are identified that are associated with AD phenotypes in iPSC neurons, and relevant associations are validated in brain. The data presented establish this iPSC collection as a resource for investigating person-specific processes in the brain that can aid in identifying and validating molecular pathways underlying AD.
    MeSH term(s) Aged ; Alzheimer Disease/metabolism ; Amyloid beta-Peptides/metabolism ; Cognition ; Humans ; Induced Pluripotent Stem Cells/metabolism ; Neurons/metabolism ; Proteomics ; tau Proteins/genetics ; tau Proteins/metabolism
    Chemical Substances Amyloid beta-Peptides ; tau Proteins
    Language English
    Publishing date 2021-09-01
    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.2021.08.003
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