13 results on '"Benetatos, Joseph"'
Search Results
2. PTEN activation contributes to neuronal and synaptic engulfment by microglia in tauopathy
- Author
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Benetatos, Joseph, Bennett, Rachel E., Evans, Harrison T., Ellis, Sevannah A., Hyman, Bradley T., Bodea, Liviu-Gabriel, and Götz, Jürgen
- Published
- 2020
- Full Text
- View/download PDF
3. Beyond the 5-HT2A Receptor: Classic and Nonclassic Targets in Psychedelic Drug Action.
- Author
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Cameron, Lindsay P., Benetatos, Joseph, Lewis, Vern, Bonniwell, Emma M., Jaster, Alaina M., Moliner, Rafael, Castrén, Eero, McCorvy, John D., Palner, Mikael, and Aguilar-Valles, Argel
- Subjects
- *
PSILOCYBIN , *HALLUCINOGENIC drugs , *POST-translational modification , *NEUROTROPHIN receptors , *SEROTONIN receptors , *DRUG derivatives , *SEROTONIN - Abstract
Serotonergic psychedelics, such as psilocybin and LSD, have garnered significant attention in recent years for their potential therapeutic effects and unique mechanisms of action. These compounds exert their primary effects through activating serotonin 5-HT2A receptors, found predominantly in cortical regions. By interacting with these receptors, serotonergic psychedelics induce alterations in perception, cognition, and emotions, leading to the characteristic psychedelic experience. One of the most crucial aspects of serotonergic psychedelics is their ability to promote neuroplasticity, the formation of new neural connections, and rewire neuronal networks. This neuroplasticity is believed to underlie their therapeutic potential for various mental health conditions, including depression, anxiety, and substance use disorders. In this mini-review, we will discuss how the 5-HT2A receptor activation is just one facet of the complex mechanisms of action of serotonergic psychedelics. They also interact with other serotonin receptor subtypes, such as 5-HT1A and 5-HT2C receptors, and with neurotrophin receptors (e.g., tropomyosin receptor kinase B). These interactions contribute to the complexity of their effects on perception, mood, and cognition. Moreover, as psychedelic research advances, there is an increasing interest in developing nonhallucinogenic derivatives of these drugs to create safer and more targeted medications for psychiatric disorders by removing the hallucinogenic properties while retaining the potential therapeutic benefits. These nonhallucinogenic derivatives would offer patients therapeutic advantages without the intense psychedelic experience, potentially reducing the risks of adverse reactions. Finally, we discuss the potential of psychedelics as substrates for post-translational modification of proteins as part of their mechanism of action. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
4. The pathophysiology of repetitive concussive traumatic brain injury in experimental models; new developments and open questions
- Author
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Brody, David L., Benetatos, Joseph, Bennett, Rachel E., Klemenhagen, Kristen C., and Mac Donald, Christine L.
- Published
- 2015
- Full Text
- View/download PDF
5. Editorial: The neuron-glia crosstalk and beyond.
- Author
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Middeldorp, Jinte, Min, Rogier, Benetatos, Joseph, and Bodea, Liviu-Gabriel
- Subjects
SCHWANN cells ,ASTROCYTES ,MICROGLIA - Published
- 2023
- Full Text
- View/download PDF
6. Ultra-High-Field Diffusion Tensor Imaging Identifies Discrete Patterns of Concussive Injury in the Rodent Brain.
- Author
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To, Xuan Vinh, Benetatos, Joseph, Soni, Neha, Liu, Dedao, Mehari Abraha, Hyab, Yan, Wenyi, Panagiotopoulou, Olga, and Nasrallah, Fatima A.
- Subjects
- *
DIFFUSION tensor imaging , *MAGNETIC resonance imaging , *POSTCONCUSSION syndrome , *BRAIN injuries , *BRAIN concussion , *LABORATORY mice , *FINITE element method - Abstract
Although concussions can result in persistent neurological post-concussion symptoms, they are typically invisible on routine magnetic resonance imaging (MRI) scans. Our study aimed to investigate the use of ultra-high-field diffusion tensor imaging (UHF-DTI) in discerning severity-dependent microstructural changes in the mouse brain following a concussion. Twenty-three C57BL/6 mice were randomly allocated into three groups: the low concussive (LC, n = 9) injury group, the high concussive (HC, n = 6) injury group, and the sham control (SC, n = 7) group. Mice were perfused on day 2 post-injury, and the brains were scanned on a 16.4T MRI scanner with UHF-DTI and neurite orientation dispersion imaging (NODDI). Finite element analysis (FEA) was performed to determine the pattern and extent of the physical impact on the brain tissue. MRI findings were correlated with histopathological analysis in a subset of mice. In the LC group, increased fractional anisotropy (FA) and decreased orientation dispersion index (ODI) but limited neurite density index (NDI) changes were found in the gray matter, and minimal changes to white matter (WM) were observed. The HC group presented increased mean diffusivity (MD), decreased NDI, and decreased ODI in the WM and gray matter (GM); decreased FA was also found in a small area of the WM. WM changes were associated with WM degeneration and neuroinflammation. FEA showed varying region-dependent degrees of stress, in line with the different imaging findings. This study provides evidence that UHF-DTI combined with NODDI can detect concussions of variable intensities. This has significant implications for the diagnosis of concussion in humans. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
7. Repetitive Concussive and Subconcussive Injury in a Human Tau Mouse Model Results in Chronic Cognitive Dysfunction and Disruption of White Matter Tracts, But Not Tau Pathology.
- Author
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Gangolli, Mihika, Benetatos, Joseph, Esparza, Thomas J., Fountain, Emeka M., Seneviratne, Shamilka, and Brody, David L.
- Subjects
- *
MAZE tests , *CHRONIC traumatic encephalopathy , *WOUNDS & injuries , *SPATIAL memory , *INTERPERSONAL relations , *PERFORMANCE - Abstract
Due to the unmet need for a means to study chronic traumatic encephalopathy (CTE) in vivo, there have been numerous efforts to develop an animal model of this progressive tauopathy. However, there is currently no consensus in the field on an injury model that consistently reproduces the neuropathological and behavioral features of CTE. We have implemented a repetitive Closed-Head Impact Model of Engineered Rotational Acceleration (CHIMERA) injury paradigm in human transgenic (hTau) mice. Animals were subjected to daily subconcussive or concussive injuries for 20 days and tested acutely, 3 months, and 12 months post-injury for deficits in social behavior, anxiety, spatial learning and memory, and depressive behavior. Animals also were assessed for chronic tau pathology, astrogliosis, and white matter degeneration. Repetitive concussive injury caused acute deficits in Morris water maze performance, including reduced swimming speed and increased distance to the platform during visible and hidden platform phases that persisted during the subacute and chronic time-points following injury. We found evidence of white matter disruption in animals injured with subconcussive and concussive injuries, with the most severe disruption occurring in the repetitive concussive injury group. Severity of white matter disruption in the corpus callosum was moderately correlated with swimming speed, while white matter disruption in the fimbria showed weak but significant correlation with worse performance during probe trial. There was no evidence of tau pathology or astrogliosis in sham or injured animals. In summary, we show that repetitive brain injury produces persistent behavioral abnormalities as late as 1 year post-injury that may be related to chronic white matter disruption, although the relationship with CTE remains to be determined. [ABSTRACT FROM AUTHOR]
- Published
- 2019
- Full Text
- View/download PDF
8. Ribosomal protein synthesis is decreased in tauopathy as revealed by noncanonical amino acid labelling: Dysregulation of protein synthesis in neurodegeneration.
- Author
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Evans, Harrison Tudor, Benetatos, Joseph, Bodea, Liviu Gabriel, and Götz, Jürgen
- Abstract
Background: Tau is a scaffolding protein which serves multiple cellular functions that are perturbed in neurodegenerative diseases, including Alzheimer's disease (AD) and frontotemporal dementia (FTD). Recently we demonstrated that amyloid‐b, the second hallmark of AD, induces de novo protein synthesis of tau, with this activation being found to be tau‐dependent. This raised the question of whether FTD‐tau by itself affects protein synthesis. Method: In order to examine protein synthesis, we optimised non‐canonical amino acid (NCAA) labelling to label newly synthesised proteins in vivo in the K369I tau transgenic K3 mouse model of FTD. Combining this technique with either fluorescent non‐canonical amino acid tagging (FUNCAT) or bio‐orthogonal non‐canonical amino acid tagging (BONCAT), we were able to visualise and purify newly synthesised proteins from mouse brain tissue. We also used polysome profiling in primary neurons to further explore the effect of tau on ribosome biogenesis. Result: Our analysis reveals massively decreased protein synthesis in neurons containing pathologically phosphorylated tau, a finding we confirmed in P301L mutant tau transgenic rTg4510 mice. Using quantitative SWATH‐MS proteomics, we identify alterations in the synthesis of 247 proteins in de novo proteome of K3 mice, including the decreased synthesis of the ribosomal subunit proteins RPL23, RPLP0, RPL19 and RPS16, a finding that was validated in both K3 and rTg4510 mice. We also demonstrate that there is a decrease in overall abundance of one of these proteins, RPL23, and that this decrease correlated with the levels of both total and AT8 phosphorylated tau. Lastly, we recapultate these findings in human tissue, with FTD‐brains showing significantly lower levels of RPL23 than healthy controls. Conclusion: Together, our findings present a potential pathomechanism by which pathological tau interferes with cellular functions through the dysregulation of ribosomal protein synthesis. [ABSTRACT FROM AUTHOR]
- Published
- 2020
- Full Text
- View/download PDF
9. Decreased synthesis of ribosomal proteins in tauopathy revealed by non‐canonical amino acid labelling.
- Author
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Evans, Harrison Tudor, Benetatos, Joseph, van Roijen, Marloes, Bodea, Liviu‐Gabriel, and Götz, Jürgen
- Subjects
- *
NEUROFIBRILLARY tangles , *RIBOSOMAL proteins , *PROTEIN synthesis , *AMINO acids , *SCAFFOLD proteins , *TAU proteins , *TRANSGENIC mice - Abstract
Tau is a scaffolding protein that serves multiple cellular functions that are perturbed in neurodegenerative diseases, including Alzheimer's disease (AD) and frontotemporal dementia (FTD). We have recently shown that amyloid‐β, the second hallmark of AD, induces de novo protein synthesis of tau. Importantly, this activation was found to be tau‐dependent, raising the question of whether FTD‐tau by itself affects protein synthesis. We therefore applied non‐canonical amino acid labelling to visualise and identify newly synthesised proteins in the K369I tau transgenic K3 mouse model of FTD. This revealed massively decreased protein synthesis in neurons containing pathologically phosphorylated tau, a finding confirmed in P301L mutant tau transgenic rTg4510 mice. Using quantitative SWATH‐MS proteomics, we identified changes in 247 proteins of the de novo proteome of K3 mice. These included decreased synthesis of the ribosomal proteins RPL23, RPLP0, RPL19 and RPS16, a finding that was validated in both K3 and rTg4510 mice. Together, our findings present a potential pathomechanism by which pathological tau interferes with cellular functions through the dysregulation of ribosomal protein synthesis. Synopsis: We demonstrate that protein synthesis is significantly decreased in the presence of frontotemporal dementia tau. Using SWATH‐MS de novo proteomics we reveal altered synthesis of distinct sets of proteins, including ribosomal proteins. Global protein synthesis is decreased in transgenic mouse models of tauopathy and this decrease correlates with tau pathology.SWATH‐MS de novo proteomics shows that distinct clusters of proteins are altered in synthesis in mice with pathological tau.Ribosomal protein synthesis is decreased in two mouse models of tauopathy and this decrease is more pronounced as disease progresses.Total abundance of the ribosomal subunit RPl23 is decreased in mouse models of tauopathy and in human FTD‐brain. [ABSTRACT FROM AUTHOR]
- Published
- 2019
- Full Text
- View/download PDF
10. DEVELOPMENT OF NEURAL STEM CELL-BASED THERAPY FOR TRAUMATIC BRAIN INJURY.
- Author
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Zhongqi Li, Oganesyan, Diana, Mooney, Rachael, Xianfang Rong, Shahmanyan, David, Benetatos, Joseph, Tsaturyan, Lusine, Najbauer, Joseph, Xiwei Wu, Barish, Michael, Brody, David, Aboody, Karen, and Gutova, Margarita
- Published
- 2016
11. A systems-biology approach connects aging mechanisms with Alzheimer's disease pathogenesis.
- Author
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Leventhal MJ, Zanella CA, Kang B, Peng J, Gritsch D, Liao Z, Bukhari H, Wang T, Pao PC, Danquah S, Benetatos J, Nehme R, Farhi S, Tsai LH, Dong X, Scherzer CR, Feany MB, and Fraenkel E
- Abstract
Age is the strongest risk factor for developing Alzheimer's disease, the most common neurodegenerative disorder. However, the mechanisms connecting advancing age to neurodegeneration in Alzheimer's disease are incompletely understood. We conducted an unbiased, genome-scale, forward genetic screen for age-associated neurodegeneration in Drosophila to identify the underlying biological processes required for maintenance of aging neurons. To connect genetic screen hits to Alzheimer's disease pathways, we measured proteomics, phosphoproteomics, and metabolomics in Drosophila models of Alzheimer's disease. We further identified Alzheimer's disease human genetic variants that modify expression in disease-vulnerable neurons. Through multi-omic, multi-species network integration of these data, we identified relationships between screen hits and tau-mediated neurotoxicity. Furthermore, we computationally and experimentally identified relationships between screen hits and DNA damage in Drosophila and human iPSC-derived neural progenitor cells. Our work identifies candidate pathways that could be targeted to attenuate the effects of age on neurodegeneration and Alzheimer's disease.
- Published
- 2024
- Full Text
- View/download PDF
12. Beyond the 5-HT 2A Receptor: Classic and Nonclassic Targets in Psychedelic Drug Action.
- Author
-
Cameron LP, Benetatos J, Lewis V, Bonniwell EM, Jaster AM, Moliner R, Castrén E, McCorvy JD, Palner M, and Aguilar-Valles A
- Subjects
- Humans, Serotonin, Receptor, Serotonin, 5-HT2A, Psilocybin, Anxiety, Hallucinogens pharmacology
- Abstract
Serotonergic psychedelics, such as psilocybin and LSD, have garnered significant attention in recent years for their potential therapeutic effects and unique mechanisms of action. These compounds exert their primary effects through activating serotonin 5-HT
2A receptors, found predominantly in cortical regions. By interacting with these receptors, serotonergic psychedelics induce alterations in perception, cognition, and emotions, leading to the characteristic psychedelic experience. One of the most crucial aspects of serotonergic psychedelics is their ability to promote neuroplasticity, the formation of new neural connections, and rewire neuronal networks. This neuroplasticity is believed to underlie their therapeutic potential for various mental health conditions, including depression, anxiety, and substance use disorders. In this mini-review, we will discuss how the 5-HT2A receptor activation is just one facet of the complex mechanisms of action of serotonergic psychedelics. They also interact with other serotonin receptor subtypes, such as 5-HT1A and 5-HT2C receptors, and with neurotrophin receptors (e.g., tropomyosin receptor kinase B). These interactions contribute to the complexity of their effects on perception, mood, and cognition. Moreover, as psychedelic research advances, there is an increasing interest in developing nonhallucinogenic derivatives of these drugs to create safer and more targeted medications for psychiatric disorders by removing the hallucinogenic properties while retaining the potential therapeutic benefits. These nonhallucinogenic derivatives would offer patients therapeutic advantages without the intense psychedelic experience, potentially reducing the risks of adverse reactions. Finally, we discuss the potential of psychedelics as substrates for post-translational modification of proteins as part of their mechanism of action., (Copyright © 2023 the authors.)- Published
- 2023
- Full Text
- View/download PDF
13. L-MYC Expression Maintains Self-Renewal and Prolongs Multipotency of Primary Human Neural Stem Cells.
- Author
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Li Z, Oganesyan D, Mooney R, Rong X, Christensen MJ, Shahmanyan D, Perrigue PM, Benetatos J, Tsaturyan L, Aramburo S, Annala AJ, Lu Y, Najbauer J, Wu X, Barish ME, Brody DL, Aboody KS, and Gutova M
- Subjects
- Animals, Brain Injuries, Traumatic metabolism, Brain Injuries, Traumatic pathology, Brain Injuries, Traumatic therapy, Cell Movement genetics, Cell Proliferation, Cell Transformation, Neoplastic genetics, Disease Models, Animal, Gene Expression Profiling, Genome-Wide Association Study, Heterografts, Humans, Mice, Neural Stem Cells pathology, Stem Cell Transplantation, Transcriptome, Transduction, Genetic, Transgenes, Cell Differentiation genetics, Cell Self Renewal genetics, Gene Expression, Genes, myc, Neural Stem Cells cytology, Neural Stem Cells metabolism
- Abstract
Pre-clinical studies indicate that neural stem cells (NSCs) can limit or reverse CNS damage through direct cell replacement, promotion of regeneration, or delivery of therapeutic agents. Immortalized NSC lines are in growing demand due to the inherent limitations of adult patient-derived NSCs, including availability, expandability, potential for genetic modifications, and costs. Here, we describe the generation and characterization of a new human fetal NSC line, immortalized by transduction with L-MYC (LM-NSC008) that in vitro displays both self-renewal and multipotent differentiation into neurons, oligodendrocytes, and astrocytes. These LM-NSC008 cells were non-tumorigenic in vivo, and migrated to orthotopic glioma xenografts in immunodeficient mice. When administered intranasally, LM-NSC008 distributed specifically to sites of traumatic brain injury (TBI). These data support the therapeutic development of immortalized LM-NSC008 cells for allogeneic use in TBI and other CNS diseases., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2016
- Full Text
- View/download PDF
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