Yazar "Gage, Fred H." seçeneğine göre listele

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    Differentiation of inflammation-responsive astrocytes from glial progenitors generated from human induced pluripotent stem cells
    (Cell Press, 2017) Santos, Renata; Vadodaria, Krishna C.; Jaeger, Baptiste N.; Mei, Arianna; Lefcochilos-Fogelquist, Sabrina; Mendes, Ana P. D.; Erikson, Galina; Shokhirev, Maxim; Randolph-Moore, Lynne; Fredlender, Callie; Dave, Sonia; Oefner, Ruth; Fitzpatrick, Conor; Pena, Monique; Barron, Jerika J.; Ku, Manching; Denli, Ahmet M.; Kerman, Bilal Ersen; Charnay, Patrick; Kelsoe, John R.; Marchetto, Maria C.; Gage, Fred H.
    Astrocyte dysfunction and neuroinflammation are detrimental features in multiple pathologies of the CNS. Therefore, the development of methods that produce functional human astrocytes represents an advance in the study of neurological diseases. Here we report an efficient method for inflammation-responsive astrocyte generation from induced pluripotent stem cells (iPSCs) and embryonic stem cells. This protocol uses an intermediate glial progenitor stage and generates functional astrocytes that show levels of glutamate uptake and calcium activation comparable with those observed in human primary astrocytes. Stimulation of stem cell-derived astrocytes with interleukin-1 beta or tumor necrosis factor a elicits a strong and rapid pro-inflammatory response. RNA-sequencing transcriptome profiling confirmed that similar gene expression changes occurred in iPSC-derived and primary astrocytes upon stimulation with interleukin-1 beta. This protocol represents an important tool for modeling in-a-dish neurological diseases with an inflammatory component, allowing for the investigation of the role of diseased astrocytes in neuronal degeneration.
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    Motoneuron expression profiling identifies an association between an axonal splice variant of HDGF-related protein 3 and peripheral myelination
    (American Society for Biochemistry and Molecular Biology Inc, 2020) Kerman, Bilal Ersen; Genoud, Stephane; Kurt Vatandaşlar, Burcu; Denli, Ahmet Murat; Ghosh, Shereen Georges; Xu, Xiangdong; Yeo, Gene W.; Aimone, James Bradley; Gage, Fred H.
    Disorders that disrupt myelin formation during development or in adulthood, such as multiple sclerosis and peripheral neuropathies, lead to severe pathologies, illustrating myelin's crucial role in normal neural functioning. However, although our understanding of glial biology is increasing, the signals that emanate from axons and regulate myelination remain largely unknown. To identify the core components of the myelination process, here we adopted a microarray analysis approach combined with laser-capture microdissection of spinal motoneurons during the myelinogenic phase of development. We identified neuronal genes whose expression was enriched during myelination and further investigated hepatoma-derived growth factor-related protein 3 (HRP3 or HDGFRP3). HRP3 was strongly expressed in the white matter fiber tracts of the peripheral (PNS) and central (CNS) nervous systems during myelination and remyelination in a cuprizone-induced demyelination model. The dynamic localization of HPR3 between axons and nuclei during myelination was consistent with its axonal localization during neuritogenesis. To study this phenomenon, we identified two splice variants encoded by theHRP3gene: the canonical isoform HRP3-I and a newly recognized isoform, HRP3-II. HRP3-I remained solely in the nucleus, whereas HRP3-II displayed distinct axonal localization both before and during myelination. Interestingly, HRP3-II remained in the nuclei of unmyelinated neurons and glial cells, suggesting the existence of a molecular machinery that transfers it to and retains it in the axons of neurons fated for myelination. Overexpression of HRP3-II, but not of HRP3-I, increased Schwann cell numbers and myelination in PNS neuron-glia co-cultures. However, HRP3-II overexpression in CNS co-cultures did not alter myelination.
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    Species-specific maturation profiles of human, chimpanzee and bonobo neural cells
    (Elife Sciences Publications Ltd, 2019) Marchetto, Maria Carolina; Hrvoj-Mihic, Branka; Kerman, Bilal Ersen; Yu, Diana X.; Vadodaria, Krishna C.; Linker, Sara B.; Narvaiza, Inigo; Santos, Renata; Denli, Ahmet M.; Mendes, Ana P. D.; Oefner, Ruth; Cook, Jonathan; McHenry, Lauren; Grasmick, Jaeson M.; Heard, Kelly; Fredlender, Callie; Randolph-Moore, Lynne; Kshirsagar, Rijul; Xenitopoulos, Rea; Chou, Grace; Hah, Nasun; Muotri, Alysson R.; Padmanabhan, Krishnan; Semendeferi, Katerina; Gage, Fred H.
    Comparative analyses of neuronal phenotypes in closely related species can shed light on neuronal changes occurring during evolution. The study of post-mortem brains of nonhuman primates (NHPs) has been limited and often does not recapitulate important species-specific developmental hallmarks. We utilize induced pluripotent stem cell (iPSC) technology to investigate the development of cortical pyramidal neurons following migration and maturation of cells grafted in the developing mouse cortex. Our results show differential migration patterns in human neural progenitor cells compared to those of chimpanzees and bonobos both in vitro and in vivo, suggesting heterochronic changes in human neurons. The strategy proposed here lays the groundwork for further comparative analyses between humans and NHPs and opens new avenues for understanding the differences in the neural underpinnings of cognition and neurological disease susceptibility between species.
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    ?-Synuclein-induced myelination deficit defines a novel interventional target for multiple system atrophy
    (Springer, 2016) Ettle, Benjamin; Kerman, Bilal Ersen; Valera-Martin, Elvira; Gillmann, Clarissa; Schlachetzki, Johannes Carolus Magnus; Reiprich, Simone; Büttner, Christian; Ekici, Arif Bülent; Reis, André; Wegner, Michael M.; Baüerle, Tobias J.; Riemenschneider, Markus Johannes; Masliah, Eliezer; Gage, Fred H.; Winkler, Jürgen
    Multiple system atrophy (MSA) is a rare atypical parkinsonian disorder characterized by a rapidly progressing clinical course and at present without any efficient therapy. Neuropathologically, myelin loss and neurodegeneration are associated with ?-synuclein accumulation in oligodendrocytes, but underlying pathomechanisms are poorly understood. Here, we analyzed the impact of oligodendrocytic ?-synuclein on the formation of myelin sheaths to define a potential interventional target for MSA. Post-mortem analyses of MSA patients and controls were performed to quantify myelin and oligodendrocyte numbers. As pre-clinical models, we used transgenic MSA mice, a myelinating stem cell-derived oligodendrocyte-neuron co-culture, and primary oligodendrocytes to determine functional consequences of oligodendrocytic ?-synuclein overexpression on myelination. We detected myelin loss accompanied by preserved or even increased numbers of oligodendrocytes in post-mortem MSA brains or transgenic mouse forebrains, respectively, indicating an oligodendrocytic dysfunction in myelin formation. Corroborating this observation, overexpression of ?-synuclein in primary and stem cell-derived oligodendrocytes severely impaired myelin formation, defining a novel ?-synuclein-linked pathomechanism in MSA. We used the pro-myelinating activity of the muscarinic acetylcholine receptor antagonist benztropine to analyze the reversibility of the myelination deficit. Transcriptome profiling of primary pre-myelinating oligodendrocytes demonstrated that benztropine readjusts myelination-related processes such as cholesterol and membrane biogenesis, being compromised by oligodendrocytic ?-synuclein. Additionally, benztropine restored the ?-synuclein-induced myelination deficit of stem cell-derived oligodendrocytes. Strikingly, benztropine also ameliorated the myelin deficit in transgenic MSA mice, resulting in a prevention of neuronal cell loss. In conclusion, this study defines the ?-synuclein-induced myelination deficit as a novel and crucial pathomechanism in MSA. Importantly, the reversible nature of this oligodendrocytic dysfunction opens a novel avenue for an intervention in MSA.