The Experts below are selected from a list of 2373 Experts worldwide ranked by ideXlab platform
Derek S Welsbie - One of the best experts on this subject based on the ideXlab platform.
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targeted disruption of dual leucine zipper kinase and leucine zipper kinase promotes neuronal survival in a model of diffuse traumatic brain injury
Molecular Neurodegeneration, 2019Co-Authors: Derek S Welsbie, Amit K Patel, Nikolaos K Ziogas, Leyan Xu, Yusong Ge, Mohamed Lehar, Athanasios S Alexandris, Nicholas Stewart, Donald J ZackAbstract:Traumatic brain injury (TBI) is a major cause of CNS neurodegeneration and has no disease-altering therapies. It is commonly associated with a specific type of biomechanical disruption of the axon called traumatic Axonal injury (TAI), which often leads to Axonal and sometimes perikaryal degeneration of CNS neurons. We have previously used genome-scale, arrayed RNA interference-based screens in primary mouse retinal ganglion cells (RGCs) to identify a pair of related kinases, dual leucine zipper kinase (DLK) and leucine zipper kinase (LZK) that are key mediators of cell death in response to simple axotomy. Moreover, we showed that DLK and LZK are the major upstream triggers for JUN N-terminal kinase (JNK) signaling following total Axonal Transection. However, the degree to which DLK/LZK are involved in TAI/TBI is unknown. Here we used the impact acceleration (IA) model of diffuse TBI, which produces TAI in the visual system, and complementary genetic and pharmacologic approaches to disrupt DLK and LZK, and explored whether DLK and LZK play a role in RGC perikaryal and Axonal degeneration in response to TAI. Our findings show that the IA model activates DLK/JNK/JUN signaling but, in contrast to axotomy, many RGCs are able to recover from the injury and terminate the activation of the pathway. Moreover, while DLK disruption is sufficient to suppress JUN phosphorylation, combined DLK and LZK inhibition is required to prevent RGC cell death. Finally, we show that the FDA-approved protein kinase inhibitor, sunitinib, which has activity against DLK and LZK, is able to produce similar increases in RGC survival. The mitogen-activated kinase kinase kinases (MAP3Ks), DLK and LZK, participate in cell death signaling of CNS neurons in response to TBI. Moreover, sustained pharmacologic inhibition of DLK is neuroprotective, an effect creating an opportunity to potentially translate these findings to patients with TBI.
Bruce D Trapp - One of the best experts on this subject based on the ideXlab platform.
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n acetylaspartate is an axon specific marker of mature white matter in vivo a biochemical and immunohistochemical study on the rat optic nerve
Annals of Neurology, 2002Co-Authors: Carl Bjartmar, Bruce D Trapp, Jan Battistuta, Nobuo Terada, Erica DupreeAbstract:Axonal pathology is a major cause of neurological disability in multiple sclerosis. Axonal Transection begins at disease onset but remains clinically silent because of compensatory brain mechanisms. Noninvasive surrogate markers for Axonal injury are therefore essential to monitor cumulative disease burden in vivo. The neuronal compound N-acetylaspartate, as measured by magnetic resonance spectroscopy, is currently the best and most specific noninvasive marker of Axonal pathology in multiple sclerosis. The possibility has been raised, however, that N-acetylaspartate is expressed also by oligodendroglial lineage cells. In order to investigate N-acetylaspartate specificity for white matter axons, transected rat optic nerves were analyzed by high-performance liquid chromatography and immunohistochemistry. In transected adult nerves, N-acetylaspartate and N-acetyl aspartylglutamate decreased in concordance with Axonal degeneration and were undetectable 24 days postTransection. Nonproliferating oligodendrocyte progenitor cells, oligodendrocytes, and myelin were abundant in these axon-free nerves. At 24 days postTransection, N-acetylaspartate was increased (42%; p = 0.02) in nontransected contralateral nerves. After Transection at postnatal day 4, total N-acetylaspartate decreased by 80% (P14; p = 0.002) and 94% (P20; p = 0.003). In these developing axon-free nerves, 25 to 33% of oligodendrocyte progenitor cells were proliferating. These data validate magnetic resonance spectroscopy measurements of N-acetylaspartate as an axon-specific monitor of central nervous system white matter in vivo. In addition, the results indicate that neuronal adaptation can increase N-acetylaspartate levels, and that 5 to 20% of the N-acetylaspartate in developing white matter is synthesized by proliferating oligodendrocyte progenitor cells.
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transected neurites apoptotic neurons and reduced inflammation in cortical multiple sclerosis lesions
Annals of Neurology, 2001Co-Authors: John W Peterson, Bruce D Trapp, Sverre Mork, Ansi ChangAbstract:Multiple Sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system that causes motor, sensory, and cognitive deficits. The present study characterized demyelinated lesions in the cerebral cortex of MS patients. One hundred twelve cortical lesions were identified in 110 tissue blocks from 50 MS patients. Three patterns of cortical demyelination were identified: Type I lesions were contiguous with subcortical white matter lesions; Type II lesions were small, confined to the cortex, and often perivascular; Type III lesions extended from the pial surface to cortical layer 3 or 4. Inflammation and neuronal pathology were studied in tissue from 8 and 7 patients, respectively. Compared to white matter lesions, cortical lesions contained 13 times fewer CD3-positive lymphocytes (195 vs 2,596/mm3 of tissue) and 6 times fewer CD68-positive microglia/macrophages (11,948 vs 67,956/mm3 of tissue). Transected neurites (both axons and dendrites) occurred at a density of 4,119/mm3 in active cortical lesions, 1,107/mm3 in chronic active cortical lesions, 25/mm3 in chronic inactive cortical lesions, 8/mm3 in myelinated MS cortex, and 1/mm3 in control cortex. In active and chronic active cortical lesions, activated microglia closely apposed and ensheathed apical dendrites, neurites, and neuronal perikarya. In addition, apoptotic neurons were increased significantly in demyelinated cortex compared to myelinated cortex. These data support the hypothesis that demyelination, Axonal Transection, dendritic Transection, and apoptotic loss of neurons in the cerebral cortex contribute to neurological dysfunction in MS patients.
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Axonal Transection in the lesions of multiple sclerosis
The New England Journal of Medicine, 1998Co-Authors: Bruce D Trapp, John W Peterson, Richard M Ransohoff, Richard A Rudick, Sverre MorkAbstract:Background Multiple sclerosis is an inflammatory demyelinating disease of the central nervous system and is the most common cause of neurologic disability in young adults. Despite antiinflammatory or immunosuppressive therapy, most patients have progressive neurologic deterioration that may reflect Axonal loss. We conducted pathological studies of brain tissues to define the changes in axons in patients with multiple sclerosis. Methods Brain tissue was obtained at autopsy from 11 patients with multiple sclerosis and 4 subjects without brain disease. Fourteen active multiple-sclerosis lesions, 33 chronic active lesions, and samples of normal-appearing white matter were examined for demyelination, inflammation, and Axonal pathologic changes by immunohistochemistry and confocal microscopy. Axonal Transection, identified by the presence of terminal Axonal ovoids, was detected in all 47 lesions and quantified in 18 lesions. Results Transected axons were a consistent feature of the lesions of multiple sclerosis...
Donald J Zack - One of the best experts on this subject based on the ideXlab platform.
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targeted disruption of dual leucine zipper kinase and leucine zipper kinase promotes neuronal survival in a model of diffuse traumatic brain injury
Molecular Neurodegeneration, 2019Co-Authors: Derek S Welsbie, Amit K Patel, Nikolaos K Ziogas, Leyan Xu, Yusong Ge, Mohamed Lehar, Athanasios S Alexandris, Nicholas Stewart, Donald J ZackAbstract:Traumatic brain injury (TBI) is a major cause of CNS neurodegeneration and has no disease-altering therapies. It is commonly associated with a specific type of biomechanical disruption of the axon called traumatic Axonal injury (TAI), which often leads to Axonal and sometimes perikaryal degeneration of CNS neurons. We have previously used genome-scale, arrayed RNA interference-based screens in primary mouse retinal ganglion cells (RGCs) to identify a pair of related kinases, dual leucine zipper kinase (DLK) and leucine zipper kinase (LZK) that are key mediators of cell death in response to simple axotomy. Moreover, we showed that DLK and LZK are the major upstream triggers for JUN N-terminal kinase (JNK) signaling following total Axonal Transection. However, the degree to which DLK/LZK are involved in TAI/TBI is unknown. Here we used the impact acceleration (IA) model of diffuse TBI, which produces TAI in the visual system, and complementary genetic and pharmacologic approaches to disrupt DLK and LZK, and explored whether DLK and LZK play a role in RGC perikaryal and Axonal degeneration in response to TAI. Our findings show that the IA model activates DLK/JNK/JUN signaling but, in contrast to axotomy, many RGCs are able to recover from the injury and terminate the activation of the pathway. Moreover, while DLK disruption is sufficient to suppress JUN phosphorylation, combined DLK and LZK inhibition is required to prevent RGC cell death. Finally, we show that the FDA-approved protein kinase inhibitor, sunitinib, which has activity against DLK and LZK, is able to produce similar increases in RGC survival. The mitogen-activated kinase kinase kinases (MAP3Ks), DLK and LZK, participate in cell death signaling of CNS neurons in response to TBI. Moreover, sustained pharmacologic inhibition of DLK is neuroprotective, an effect creating an opportunity to potentially translate these findings to patients with TBI.
Hartmut Wekerle - One of the best experts on this subject based on the ideXlab platform.
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planting and pruning in the brain mhc antigens involved in synaptic plasticity
Proceedings of the National Academy of Sciences of the United States of America, 2005Co-Authors: Hartmut WekerleAbstract:MHC antigens count among the classical “immune” molecules. They act as platforms presenting antigenic peptides to the specific receptors on T cells. MHC class I molecules interact with the CD8+ “killer” T cell lineage, whereas class II molecules present antigen to CD4 “helper” T cells. In addition, some MHC proteins can be recognized by natural killer (NK) cells, where, depending on the nature and context of a particular receptor, they trigger either activating or suppressive signals. Additional roles such as in embryonic development or tissue organization have been postulated, but so far these hypotheses have not stood the test of molecular immunology (1). Now, this trend seems to be changing. In a recent issue of PNAS, Oliveira et al. (2) reported that MHC class I or Ib antigens are required to regulate synaptic pruning on neuronal bodies that undergo retrograde degeneration after Axonal Transection. A role of MHC determinants in neural tissue response is surprising because, according to an imperial dogma, MHC determinants are missing in the CNS. The lack of MHC is one major factor interfering with immune reactivity in the healthy CNS, securing the brain's “immune privilege.” However, this is not the entire story, because MHC products, along with many other “immune” genes, are readily inducible in the CNS tissues under various pathological conditions, including autoimmune inflammation, microbial infection, and neuronal degeneration. The surprising relationship between brain degeneration and immune reactivity has been strikingly demonstrated …
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planting and pruning in the brain mhc antigens involved in synaptic plasticity
Proceedings of the National Academy of Sciences of the United States of America, 2005Co-Authors: Hartmut WekerleAbstract:MHC antigens count among the classical “immune” molecules. They act as platforms presenting antigenic peptides to the specific receptors on T cells. MHC class I molecules interact with the CD8+ “killer” T cell lineage, whereas class II molecules present antigen to CD4 “helper” T cells. In addition, some MHC proteins can be recognized by natural killer (NK) cells, where, depending on the nature and context of a particular receptor, they trigger either activating or suppressive signals. Additional roles such as in embryonic development or tissue organization have been postulated, but so far these hypotheses have not stood the test of molecular immunology (1). Now, this trend seems to be changing. In a recent issue of PNAS, Oliveira et al. (2) reported that MHC class I or Ib antigens are required to regulate synaptic pruning on neuronal bodies that undergo retrograde degeneration after Axonal Transection.
Amit K Patel - One of the best experts on this subject based on the ideXlab platform.
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targeted disruption of dual leucine zipper kinase and leucine zipper kinase promotes neuronal survival in a model of diffuse traumatic brain injury
Molecular Neurodegeneration, 2019Co-Authors: Derek S Welsbie, Amit K Patel, Nikolaos K Ziogas, Leyan Xu, Yusong Ge, Mohamed Lehar, Athanasios S Alexandris, Nicholas Stewart, Donald J ZackAbstract:Traumatic brain injury (TBI) is a major cause of CNS neurodegeneration and has no disease-altering therapies. It is commonly associated with a specific type of biomechanical disruption of the axon called traumatic Axonal injury (TAI), which often leads to Axonal and sometimes perikaryal degeneration of CNS neurons. We have previously used genome-scale, arrayed RNA interference-based screens in primary mouse retinal ganglion cells (RGCs) to identify a pair of related kinases, dual leucine zipper kinase (DLK) and leucine zipper kinase (LZK) that are key mediators of cell death in response to simple axotomy. Moreover, we showed that DLK and LZK are the major upstream triggers for JUN N-terminal kinase (JNK) signaling following total Axonal Transection. However, the degree to which DLK/LZK are involved in TAI/TBI is unknown. Here we used the impact acceleration (IA) model of diffuse TBI, which produces TAI in the visual system, and complementary genetic and pharmacologic approaches to disrupt DLK and LZK, and explored whether DLK and LZK play a role in RGC perikaryal and Axonal degeneration in response to TAI. Our findings show that the IA model activates DLK/JNK/JUN signaling but, in contrast to axotomy, many RGCs are able to recover from the injury and terminate the activation of the pathway. Moreover, while DLK disruption is sufficient to suppress JUN phosphorylation, combined DLK and LZK inhibition is required to prevent RGC cell death. Finally, we show that the FDA-approved protein kinase inhibitor, sunitinib, which has activity against DLK and LZK, is able to produce similar increases in RGC survival. The mitogen-activated kinase kinase kinases (MAP3Ks), DLK and LZK, participate in cell death signaling of CNS neurons in response to TBI. Moreover, sustained pharmacologic inhibition of DLK is neuroprotective, an effect creating an opportunity to potentially translate these findings to patients with TBI.