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  1. Article: Modeling Protein Aggregation and the Heat Shock Response in ALS iPSC-Derived Motor Neurons.

    Seminary, Emily R / Sison, Samantha L / Ebert, Allison D

    Frontiers in neuroscience

    2018  Volume 12, Page(s) 86

    Abstract: Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder caused by the selective loss of the upper and lower motor neurons. Only 10% of all cases are caused by a mutation in one of the two dozen different identified genes, while ... ...

    Abstract Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder caused by the selective loss of the upper and lower motor neurons. Only 10% of all cases are caused by a mutation in one of the two dozen different identified genes, while the remaining 90% are likely caused by a combination of as yet unidentified genetic and environmental factors. Mutations in
    Language English
    Publishing date 2018-02-20
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2411902-7
    ISSN 1662-453X ; 1662-4548
    ISSN (online) 1662-453X
    ISSN 1662-4548
    DOI 10.3389/fnins.2018.00086
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Studying Human Neurological Disorders Using Induced Pluripotent Stem Cells: From 2D Monolayer to 3D Organoid and Blood Brain Barrier Models.

    Logan, Sarah / Arzua, Thiago / Canfield, Scott G / Seminary, Emily R / Sison, Samantha L / Ebert, Allison D / Bai, Xiaowen

    Comprehensive Physiology

    2019  Volume 9, Issue 2, Page(s) 565–611

    Abstract: Neurological disorders have emerged as a predominant healthcare concern in recent years due to their severe consequences on quality of life and prevalence throughout the world. Understanding the underlying mechanisms of these diseases and the ... ...

    Abstract Neurological disorders have emerged as a predominant healthcare concern in recent years due to their severe consequences on quality of life and prevalence throughout the world. Understanding the underlying mechanisms of these diseases and the interactions between different brain cell types is essential for the development of new therapeutics. Induced pluripotent stem cells (iPSCs) are invaluable tools for neurological disease modeling, as they have unlimited self-renewal and differentiation capacity. Mounting evidence shows: (i) various brain cells can be generated from iPSCs in two-dimensional (2D) monolayer cultures; and (ii) further advances in 3D culture systems have led to the differentiation of iPSCs into organoids with multiple brain cell types and specific brain regions. These 3D organoids have gained widespread attention as in vitro tools to recapitulate complex features of the brain, and (iii) complex interactions between iPSC-derived brain cell types can recapitulate physiological and pathological conditions of blood-brain barrier (BBB). As iPSCs can be generated from diverse patient populations, researchers have effectively applied 2D, 3D, and BBB models to recapitulate genetically complex neurological disorders and reveal novel insights into molecular and genetic mechanisms of neurological disorders. In this review, we describe recent progress in the generation of 2D, 3D, and BBB models from iPSCs and further discuss their limitations, advantages, and future ventures. This review also covers the current status of applications of 2D, 3D, and BBB models in drug screening, precision medicine, and modeling a wide range of neurological diseases (e.g., neurodegenerative diseases, neurodevelopmental disorders, brain injury, and neuropsychiatric disorders). © 2019 American Physiological Society. Compr Physiol 9:565-611, 2019.
    MeSH term(s) Animals ; Blood-Brain Barrier ; Cell Culture Techniques ; Drug Evaluation, Preclinical ; Humans ; Induced Pluripotent Stem Cells ; Mental Disorders ; Models, Biological ; Nervous System Diseases ; Organoids ; Precision Medicine
    Language English
    Publishing date 2019-03-14
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
    ISSN 2040-4603
    ISSN (online) 2040-4603
    DOI 10.1002/cphy.c180025
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Human Cytomegalovirus Disruption of Calcium Signaling in Neural Progenitor Cells and Organoids.

    Sison, Samantha L / O'Brien, Benjamin S / Johnson, Amanda J / Seminary, Emily R / Terhune, Scott S / Ebert, Allison D

    Journal of virology

    2019  Volume 93, Issue 17

    Abstract: The herpesvirus human cytomegalovirus (HCMV) is a leading cause of congenital birth defects. Infection can result in infants born with a variety of symptoms, including hepatosplenomegaly, microcephaly, and developmental disabilities. Microcephaly is ... ...

    Abstract The herpesvirus human cytomegalovirus (HCMV) is a leading cause of congenital birth defects. Infection can result in infants born with a variety of symptoms, including hepatosplenomegaly, microcephaly, and developmental disabilities. Microcephaly is associated with disruptions in the neural progenitor cell (NPC) population. Here, we defined the impact of HCMV infection on neural tissue development and calcium regulation, a critical activity in neural development. Regulation of intracellular calcium involves purinergic receptors and voltage-gated calcium channels (VGCC). HCMV infection compromised the ability of both pathways in NPCs as well as fibroblasts to respond to stimulation. We observed significant drops in basal calcium levels in infected NPCs which were accompanied by loss in VGCC activity and purinergic receptor responses. However, uninfected cells in the population retained responsiveness. Addition of the HCMV inhibitor maribavir reduced viral spread but failed to restore activity in infected cells. To study neural development, we infected three-dimensional cortical organoids with HCMV. Infection spread to a subset of cells over time and disrupted organoid structure, with alterations in developmental and neural layering markers. Organoid-derived infected neurons and astrocytes were unable to respond to stimulation whereas uninfected cells retained nearly normal responses. Maribavir partially restored structural features, including neural rosette formation, and dampened the impact of infection on neural cellular function. Using a tissue model system, we have demonstrated that HCMV alters cortical neural layering and disrupts calcium regulation in infected cells.
    MeSH term(s) Benzimidazoles/pharmacology ; Calcium Signaling ; Cell Differentiation ; Cell Line ; Cytomegalovirus/drug effects ; Cytomegalovirus/pathogenicity ; Cytomegalovirus/physiology ; Cytomegalovirus Infections/metabolism ; Humans ; Induced Pluripotent Stem Cells/cytology ; Neural Stem Cells/cytology ; Neural Stem Cells/metabolism ; Neural Stem Cells/virology ; Organ Culture Techniques ; Organoids/cytology ; Organoids/metabolism ; Organoids/virology ; Receptors, Purinergic/metabolism ; Ribonucleosides/pharmacology ; Virus Replication/drug effects ; Voltage-Gated Sodium Channels/metabolism
    Chemical Substances Benzimidazoles ; Receptors, Purinergic ; Ribonucleosides ; Voltage-Gated Sodium Channels ; maribavir (PTB4X93HE1)
    Language English
    Publishing date 2019-08-13
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 80174-4
    ISSN 1098-5514 ; 0022-538X
    ISSN (online) 1098-5514
    ISSN 0022-538X
    DOI 10.1128/JVI.00954-19
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 609: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (1.OG)
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  4. Article ; Online: Motor Neuron Generation from iPSCs from Identical Twins Discordant for Amyotrophic Lateral Sclerosis.

    Seminary, Emily R / Santarriaga, Stephanie / Wheeler, Lynn / Mejaki, Marie / Abrudan, Jenica / Demos, Wendy / Zimmermann, Michael T / Urrutia, Raul A / Fee, Dominic / Barkhaus, Paul E / Ebert, Allison D

    Cells

    2020  Volume 9, Issue 3

    Abstract: Amyotrophic lateral sclerosis (ALS) is a complex neurodegenerative disorder characterized by the loss of the upper and lower motor neurons. Approximately 10% of cases are caused by specific mutations in known genes, with the remaining cases having no ... ...

    Abstract Amyotrophic lateral sclerosis (ALS) is a complex neurodegenerative disorder characterized by the loss of the upper and lower motor neurons. Approximately 10% of cases are caused by specific mutations in known genes, with the remaining cases having no known genetic link. As such, sporadic cases have been more difficult to model experimentally. Here, we describe the generation and differentiation of ALS induced pluripotent stem cells reprogrammed from discordant identical twins. Whole genome sequencing revealed no relevant mutations in known ALS-causing genes that differ between the twins. As protein aggregation is found in all ALS patients and is thought to contribute to motor neuron death, we sought to characterize the aggregation phenotype of the sporadic ALS induced pluripotent stem cells (iPSCs). Motor neurons from both twins had high levels of insoluble proteins that commonly aggregate in ALS that did not robustly change in response to exogenous glutamate. In contrast, established genetic ALS iPSC lines demonstrated insolubility in a protein- and genotype-dependent manner. Moreover, whereas the genetic ALS lines failed to induce autophagy after glutamate stress, motor neurons from both twins and independent controls did activate this protective pathway. Together, these data indicate that our unique model of sporadic ALS may provide key insights into disease pathology and highlight potential differences between sporadic and familial ALS.
    MeSH term(s) Amyotrophic Lateral Sclerosis/genetics ; Amyotrophic Lateral Sclerosis/pathology ; Autophagy ; Cell Survival ; Glutamic Acid/metabolism ; Humans ; Induced Pluripotent Stem Cells/pathology ; Male ; Middle Aged ; Motor Neurons/metabolism ; Motor Neurons/pathology ; Protein Aggregates ; Solubility ; Twins, Monozygotic ; Whole Genome Sequencing
    Chemical Substances Protein Aggregates ; Glutamic Acid (3KX376GY7L)
    Language English
    Publishing date 2020-02-28
    Publishing country Switzerland
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2661518-6
    ISSN 2073-4409 ; 2073-4409
    ISSN (online) 2073-4409
    ISSN 2073-4409
    DOI 10.3390/cells9030571
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  5. Article ; Online: Astrocyte-produced miR-146a as a mediator of motor neuron loss in spinal muscular atrophy.

    Sison, Samantha L / Patitucci, Teresa N / Seminary, Emily R / Villalon, Eric / Lorson, Christian L / Ebert, Allison D

    Human molecular genetics

    2017  Volume 26, Issue 17, Page(s) 3409–3420

    Abstract: Spinal muscular atrophy (SMA), the leading genetic cause of infant mortality, is caused by the loss of the survival motor neuron-1 (SMN1) gene, which leads to motor neuron loss, muscle atrophy, respiratory distress, and death. Motor neurons exhibit the ... ...

    Abstract Spinal muscular atrophy (SMA), the leading genetic cause of infant mortality, is caused by the loss of the survival motor neuron-1 (SMN1) gene, which leads to motor neuron loss, muscle atrophy, respiratory distress, and death. Motor neurons exhibit the most profound loss, but the mechanisms underlying disease pathogenesis are not fully understood. Recent evidence suggests that motor neuron extrinsic influences, such as those arising from astrocytes, contribute to motor neuron malfunction and loss. Here we investigated both loss-of-function and toxic gain-of-function astrocyte mechanisms that could play a role in SMA pathology. We had previously found that glial derived neurotrophic factor (GDNF) is reduced in SMA astrocytes. However, reduced GDNF expression does not play a major role in SMA pathology as viral-mediated GDNF re-expression did not improve astrocyte function or motor neuron loss. In contrast, we found that SMA astrocytes increased microRNA (miR) production and secretion compared to control astrocytes, suggesting potential toxic gain-of-function properties. Specifically, we found that miR-146a was significantly upregulated in SMA induced pluripotent stem cell (iPSC)-derived astrocytes and SMNΔ7 mouse spinal cord. Moreover, increased miR-146a was sufficient to induce motor neuron loss in vitro, whereas miR-146a inhibition prevented SMA astrocyte-induced motor neuron loss. Together, these data indicate that altered astrocyte production of miR-146a may be a contributing factor in astrocyte-mediated SMA pathology.
    Language English
    Publishing date 2017-09-01
    Publishing country England
    Document type Journal Article
    ZDB-ID 1108742-0
    ISSN 1460-2083 ; 0964-6906
    ISSN (online) 1460-2083
    ISSN 0964-6906
    DOI 10.1093/hmg/ddx230
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    In stock of ZB MED Cologne/Königswinter

    Zs.A 3469: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (2.OG)
    ab Jg. 2022: Lesesaal (EG)

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  6. Article: SRCP1 Conveys Resistance to Polyglutamine Aggregation

    Santarriaga, Stephanie / Haver, Holly N / Kanack, Adam J / Fikejs, Alicia S / Sison, Samantha L / Egner, John M / Bostrom, Jonathan R / Seminary, Emily R / Hill, R. Blake / Link, Brian A / Ebert, Allison D / Scaglione, K. Matthew

    Molecular cell. 2018 July 19, v. 71, no. 2

    2018  

    Abstract: The polyglutamine (polyQ) diseases are a group of nine neurodegenerative diseases caused by the expansion of a polyQ tract that results in protein aggregation. Unlike other model organisms, Dictyostelium discoideum is a proteostatic outlier, naturally ... ...

    Abstract The polyglutamine (polyQ) diseases are a group of nine neurodegenerative diseases caused by the expansion of a polyQ tract that results in protein aggregation. Unlike other model organisms, Dictyostelium discoideum is a proteostatic outlier, naturally encoding long polyQ tracts yet resistant to polyQ aggregation. Here we identify serine-rich chaperone protein 1 (SRCP1) as a molecular chaperone that is necessary and sufficient to suppress polyQ aggregation. SRCP1 inhibits aggregation of polyQ-expanded proteins, allowing for their degradation via the proteasome, where SRCP1 is also degraded. SRCP1’s C-terminal domain is essential for its activity in cells, and peptides that mimic this domain suppress polyQ aggregation in vitro. Together our results identify a novel type of molecular chaperone and reveal how nature has dealt with the problem of polyQ aggregation.
    Keywords Dictyostelium discoideum ; amino acid sequences ; models ; molecular chaperones ; neurodegenerative diseases ; peptides ; proteasome endopeptidase complex
    Language English
    Dates of publication 2018-0719
    Size p. 216-228.e7.
    Publishing place Elsevier Inc.
    Document type Article
    ZDB-ID 1415236-8
    ISSN 1097-4164 ; 1097-2765
    ISSN (online) 1097-4164
    ISSN 1097-2765
    DOI 10.1016/j.molcel.2018.07.008
    Database NAL-Catalogue (AGRICOLA)

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  7. Article ; Online: SRCP1 Conveys Resistance to Polyglutamine Aggregation.

    Santarriaga, Stephanie / Haver, Holly N / Kanack, Adam J / Fikejs, Alicia S / Sison, Samantha L / Egner, John M / Bostrom, Jonathan R / Seminary, Emily R / Hill, R Blake / Link, Brian A / Ebert, Allison D / Scaglione, K Matthew

    Molecular cell

    2018  Volume 71, Issue 2, Page(s) 216–228.e7

    Abstract: The polyglutamine (polyQ) diseases are a group of nine neurodegenerative diseases caused by the expansion of a polyQ tract that results in protein aggregation. Unlike other model organisms, Dictyostelium discoideum is a proteostatic outlier, naturally ... ...

    Abstract The polyglutamine (polyQ) diseases are a group of nine neurodegenerative diseases caused by the expansion of a polyQ tract that results in protein aggregation. Unlike other model organisms, Dictyostelium discoideum is a proteostatic outlier, naturally encoding long polyQ tracts yet resistant to polyQ aggregation. Here we identify serine-rich chaperone protein 1 (SRCP1) as a molecular chaperone that is necessary and sufficient to suppress polyQ aggregation. SRCP1 inhibits aggregation of polyQ-expanded proteins, allowing for their degradation via the proteasome, where SRCP1 is also degraded. SRCP1's C-terminal domain is essential for its activity in cells, and peptides that mimic this domain suppress polyQ aggregation in vitro. Together our results identify a novel type of molecular chaperone and reveal how nature has dealt with the problem of polyQ aggregation.
    MeSH term(s) Cell Line ; Dictyostelium/metabolism ; HEK293 Cells ; Humans ; Molecular Chaperones/metabolism ; Peptides/metabolism ; Proteasome Endopeptidase Complex/metabolism ; Protein Binding ; Serine/metabolism ; Ubiquitin/metabolism
    Chemical Substances Molecular Chaperones ; Peptides ; Ubiquitin ; polyglutamine (26700-71-0) ; Serine (452VLY9402) ; Proteasome Endopeptidase Complex (EC 3.4.25.1)
    Language English
    Publishing date 2018-07-19
    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.2018.07.008
    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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