Potential Role of Drebrin A, an F-Actin Binding Protein, in Reactive Synaptic Plasticity after Pilocarpine-Induced Seizures: Functional Implications in Epilepsy

Several neurological disorders characterized by cognitive deficits, including Alzheimer's disease, down syndrome, and epilepsy exhibit abnormal spine density and/or morphology. Actin-based cytoskeleton network dynamics is critical for the regulation of spine morphology and synaptic function. In this paper, I consider the functions of drebrin A in cell shaping, spine plasticity, and synaptic function. Developmentally regulated brain protein (drebrin A) is one of the most abundant neuron-specific binding proteins of F-actin and its expression is increased in parallel with synapse formation. Drebrin A is particularly concentrated in dendritic spines receiving excitatory inputs. Our recent findings point to a critical role of DA in dendritic spine structural integrity and stabilization, likely via regulation of actin cytoskeleton dynamics, and glutamatergic synaptic function that underlies the development of spontaneous recurrent seizures in pilocarpine-treated animals. Further research into this area may provide useful insights into the pathology of status epilepticus and epileptogenic mechanisms and ultimately may provide the basis for future treatment options.

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The Emerging Role of Glucagon-like Peptide-1 Receptor Agonists for the Management of NAFLD

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/clinem/dgab578 ◽

2021 ◽

Author(s):

Chandani Patel Chavez ◽

Kenneth Cusi ◽

Sushma Kadiyala

Keyword(s):

Evidence Synthesis ◽

Clinical Care ◽

Treatment Options ◽

Critical Role ◽

Risk Groups ◽

The United States ◽

Multidisciplinary Teams ◽

Consensus Statements ◽

Meta Analyses

Abstract Context The burden of cirrhosis from NAFLD is reaching epidemic proportions in the United States. This calls for greater awareness among endocrinologists, who often see but may miss the diagnosis in adults with obesity or type 2 diabetes mellitus (T2D) who are at the highest risk. At the same time, recent studies suggest that GLP-1RAs are beneficial versus steatohepatitis (NASH) in this population. This minireview aims to assist endocrinologists to recognize the condition and recent work on the role of GLP-1RAs in NAFLD/NASH. Evidence acquisition Evidence from observational studies, randomized controlled trials, and meta-analyses. Evidence Synthesis Endocrinologists should lead multidisciplinary teams to implement recent consensus statements on NAFLD that call for screening and treatment of clinically significant fibrosis to prevent cirrhosis, especially in the high-risk groups (i.e., people with obesity, prediabetes or T2D). With no FDA-approved agents, weight loss is central to their successful management, with pharmacological treatment options limited today to vitamin E (in people without T2D) and diabetes medications that reverse steatohepatitis, such as pioglitazone or GLP-1RA. Recently the benefit of GLP-1RAs in NAFLD, suggested from earlier trials, has been confirmed in adults with biopsy-proven NASH. In 2021, the FDA also approved semaglutide for obesity management. Conclusion A paradigm change is developing between the endocrinologist’s greater awareness about their critical role to curve the epidemic of NAFLD and new clinical care pathways that include a broader use of GLP-1RAs in the management of these complex patients.

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Regulation of Phosphorylated State of NMDA Receptor by STEP61 Phosphatase after Mild-Traumatic Brain Injury: Role of Oxidative Stress

Antioxidants ◽

10.3390/antiox10101575 ◽

2021 ◽

Vol 10 (10) ◽

pp. 1575

Author(s):

Francisco J. Carvajal ◽

Waldo Cerpa

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Tyrosine Phosphatase ◽

Critical Role ◽

Synaptic Function ◽

Fyn Kinase ◽

Impact Device ◽

Traumatic Lesions ◽

Early Biomarker

Traumatic Brain Injury (TBI) mediates neuronal death through several events involving many molecular pathways, including the glutamate-mediated excitotoxicity for excessive stimulation of N-methyl-D-aspartate receptors (NMDARs), producing activation of death signaling pathways. However, the contribution of NMDARs (distribution and signaling-associated to the distribution) remains incompletely understood. We propose a critical role of STEP61 (Striatal-Enriched protein tyrosine phosphatase) in TBI; this phosphatase regulates the dephosphorylated state of the GluN2B subunit through two pathways: by direct dephosphorylation of tyrosine-1472 and indirectly via dephosphorylation and inactivation of Fyn kinase. We previously demonstrated oxidative stress’s contribution to NMDAR signaling and distribution using SOD2+/− mice such a model. We performed TBI protocol using a controlled frontal impact device using C57BL/6 mice and SOD2+/− animals. After TBI, we found alterations in cognitive performance, NMDAR-dependent synaptic function (decreased synaptic form of NMDARs and decreased synaptic current NMDAR-dependent), and increased STEP61 activity. These changes are reduced partially with the STEP61-inhibitor TC-2153 treatment in mice subjected to TBI protocol. This study contributes with evidence about the role of STEP61 in the neuropathological progression after TBI and also the alteration in their activity, such as an early biomarker of synaptic damage in traumatic lesions.

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Emerging roles of the Hedgehog signalling pathway in inflammatory bowel disease

Cell Death Discovery ◽

10.1038/s41420-021-00679-7 ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Zhuo Xie ◽

Mudan Zhang ◽

Gaoshi Zhou ◽

Lihui Lin ◽

Jing Han ◽

...

Keyword(s):

Inflammatory Bowel Disease ◽

Bowel Disease ◽

Molecular Mechanisms ◽

Treatment Options ◽

Critical Role ◽

Signalling Pathway ◽

Hedgehog Signalling Pathway ◽

Inflammatory Bowel ◽

Effective Drugs

AbstractThe Hedgehog (Hh) signalling pathway plays a critical role in the growth and patterning during embryonic development and maintenance of adult tissue homeostasis. Emerging data indicate that Hh signalling is implicated in the pathogenesis of inflammatory bowel disease (IBD). Current therapeutic treatments for IBD require optimisation, and novel effective drugs are warranted. Targeting the Hh signalling pathway may pave the way for successful IBD treatment. In this review, we introduce the molecular mechanisms underlying the Hh signalling pathway and its role in maintaining intestinal homeostasis. Then, we present interactions between the Hh signalling and other pathways involved in IBD and colitis-associated colorectal cancer (CAC), such as the Wnt and nuclear factor-kappa B (NF-κB) pathways. Furthermore, we summarise the latest research on Hh signalling associated with the occurrence and progression of IBD and CAC. Finally, we discuss the future directions for research on the role of Hh signalling in IBD pathogenesis and provide viewpoints on novel treatment options for IBD by targeting Hh signalling. An in-depth understanding of the complex role of Hh signalling in IBD pathogenesis will contribute to the development of new effective therapies for IBD patients.

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Vimentin filaments drive migratory persistence in polyploidal cancer cells

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2011912117 ◽

2020 ◽

Vol 117 (43) ◽

pp. 26756-26765

Author(s):

Botai Xuan ◽

Deepraj Ghosh ◽

Joy Jiang ◽

Rachelle Shao ◽

Michelle R. Dawson

Keyword(s):

Cancer Cells ◽

Cancer Progression ◽

Structural Integrity ◽

Single Cell Analysis ◽

Critical Role ◽

Critical Function ◽

Rna Knockdown ◽

Interfering Rna ◽

The Impact

Polyploidal giant cancer cells (PGCCs) are multinucleated chemoresistant cancer cells found in heterogeneous solid tumors. Due in part to their apparent dormancy, the effect of PGCCs on cancer progression has remained largely unstudied. Recent studies have highlighted the critical role of PGCCs as aggressive and chemoresistant cancer cells, as well as their ability to undergo amitotic budding to escape dormancy. Our recent study demonstrated the unique biophysical properties of PGCCs, as well as their unusual migratory persistence. Here we unveil the critical function of vimentin intermediate filaments (VIFs) in maintaining the structural integrity of PGCCs and enhancing their migratory persistence. We performed in-depth single-cell analysis to examine the distribution of VIFs and their role in migratory persistence. We found that PGCCs rely heavily on their uniquely distributed and polarized VIF network to enhance their transition from a jammed to an unjammed state to allow for directional migration. Both the inhibition of VIFs with acrylamide and small interfering RNA knockdown of vimentin significantly decreased PGCC migration and resulted in a loss of PGCC volume. Because PGCCs rely on their VIF network to direct migration and to maintain their enlarged morphology, targeting vimentin or vimentin cross-linking proteins could provide a therapeutic approach to mitigate the impact of these chemoresistant cells in cancer progression and to improve patient outcomes with chemotherapy.

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Right Place at the Right Time: How Changes in Protocadherins Affect Synaptic Connections Contributing to the Etiology of Neurodevelopmental Disorders

Cells ◽

10.3390/cells9122711 ◽

2020 ◽

Vol 9 (12) ◽

pp. 2711

Author(s):

Maria Mancini ◽

Silvia Bassani ◽

Maria Passafaro

Keyword(s):

Cell Adhesion ◽

Neurodevelopmental Disorders ◽

Synapse Formation ◽

Large Fraction ◽

Critical Role ◽

Basic Research ◽

Axon Pathfinding ◽

Neurite Initiation ◽

The Right

During brain development, neurons need to form the correct connections with one another in order to give rise to a functional neuronal circuitry. Mistakes during this process, leading to the formation of improper neuronal connectivity, can result in a number of brain abnormalities and impairments collectively referred to as neurodevelopmental disorders. Cell adhesion molecules (CAMs), present on the cell surface, take part in the neurodevelopmental process regulating migration and recognition of specific cells to form functional neuronal assemblies. Among CAMs, the members of the protocadherin (PCDH) group stand out because they are involved in cell adhesion, neurite initiation and outgrowth, axon pathfinding and fasciculation, and synapse formation and stabilization. Given the critical role of these macromolecules in the major neurodevelopmental processes, it is not surprising that clinical and basic research in the past two decades has identified several PCDH genes as responsible for a large fraction of neurodevelopmental disorders. In the present article, we review these findings with a focus on the non-clustered PCDH sub-group, discussing the proteins implicated in the main neurodevelopmental disorders.

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PUFA and their derivatives in neurotransmission and synapses: a new hallmark of synaptopathies

Proceedings of The Nutrition Society ◽

10.1017/s0029665120000129 ◽

2020 ◽

Vol 79 (4) ◽

pp. 388-403

Author(s):

Mathieu Di Miceli ◽

Clémentine Bosch-Bouju ◽

Sophie Layé

Keyword(s):

Synapse Formation ◽

Synaptic Function ◽

Past Century ◽

High Concentration ◽

Dietary Pufa ◽

Synaptic Functions ◽

Neuropsychiatric Diseases ◽

Optimal Function ◽

The Brain

PUFA of the n-3 and n-6 families are present in high concentration in the brain where they are major components of cell membranes. The main forms found in the brain are DHA (22 :6, n-3) and arachidonic acid (20:4, n-6). In the past century, several studies pinpointed that modifications of n-3 and n-6 PUFA levels in the brain through dietary supply or genetic means are linked to the alterations of synaptic function. Yet, synaptopathies emerge as a common characteristic of neurodevelopmental disorders, neuropsychiatric diseases and some neurodegenerative diseases. Understanding the mechanisms of action underlying the activity of PUFA at the level of synapses is thus of high interest. In this frame, dietary supplementation in PUFA aiming at restoring or promoting the optimal function of synapses appears as a promising strategy to treat synaptopathies. This paper reviews the link between dietary PUFA, synapse formation and the role of PUFA and their metabolites in synaptic functions.

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TheGαoActivator Mastoparan-7 Promotes Dendritic Spine Formation in Hippocampal Neurons

Neural Plasticity ◽

10.1155/2016/4258171 ◽

2016 ◽

Vol 2016 ◽

pp. 1-11 ◽

Cited By ~ 7

Author(s):

Valerie T. Ramírez ◽

Eva Ramos-Fernández ◽

Nibaldo C. Inestrosa

Keyword(s):

Protein Kinase ◽

Dendritic Spine ◽

Hippocampal Neurons ◽

Biological Effects ◽

Critical Role ◽

Head Width ◽

Dependent Manner ◽

Spine Density ◽

Dendritic Spine Density

Mastoparan-7 (Mas-7), an analogue of the peptide mastoparan, which is derived from wasp venom, is a direct activator ofPertussis toxin-(PTX-) sensitive G proteins. Mas-7 produces several biological effects in different cell types; however, little is known about how Mas-7 influences mature hippocampal neurons. We examined the specific role of Mas-7 in the development of dendritic spines, the sites of excitatory synaptic contact that are crucial for synaptic plasticity. We report here that exposure of hippocampal neurons to a low dose of Mas-7 increases dendritic spine density and spine head width in a time-dependent manner. Additionally, Mas-7 enhances postsynaptic density protein-95 (PSD-95) clustering in neurites and activatesGαosignaling, increasing the intracellular Ca2+concentration. To define the role of signaling intermediates, we measured the levels of phosphorylated protein kinase C (PKC), c-Jun N-terminal kinase (JNK), and calcium-calmodulin dependent protein kinase IIα(CaMKIIα) after Mas-7 treatment and determined that CaMKII activation is necessary for the Mas-7-dependent increase in dendritic spine density. Our results demonstrate a critical role forGαosubunit signaling in the regulation of synapse formation.

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A critical role of Rho-kinase ROCK2 in the regulation of spine and synaptic function

Neuropharmacology ◽

10.1016/j.neuropharm.2008.07.031 ◽

2009 ◽

Vol 56 (1) ◽

pp. 81-89 ◽

Cited By ~ 55

Author(s):

Zikai Zhou ◽

Yanghong Meng ◽

Suhail Asrar ◽

Zarko Todorovski ◽

Zhengping Jia

Keyword(s):

Critical Role ◽

Rho Kinase ◽

Synaptic Function

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Electric field mediated fibronectin-hydroxyapatite interaction: A molecular insight

10.1101/2020.07.22.215327 ◽

2020 ◽

Author(s):

Subhadip Basu ◽

Biswajit Gorai ◽

Bikramjit Basu ◽

Prabal K. Maiti

Keyword(s):

Field Strength ◽

Electric Field ◽

Protein Adsorption ◽

Structural Integrity ◽

Critical Role ◽

Field Stimulation ◽

Electric Field Stimulation ◽

Cell Material ◽

Material Interaction

AbstractIn experimental research driven biomaterials science, the influence of different material properties (elastic stiffness, surface energy, etc.), and to a relatively lesser extent, the biophysical stimulation (electric/magnetic) on the cell-material interaction has been extensively investigated. Considering the central importance of the protein adsorption on cell-material interaction, the role of physiochemical factors on the protein adsorption is also probed. Despite its significance, the quantitative analysis of many such aspects remains largely unexplored in biomaterials science. In recent studies, the critical role of electric field stimulation towards modulation of cell functionality on implantable biomaterials has been experimentally demonstrated. Given this background, we investigated the influence of external electric field stimulation (upto 1.00 V/nm) on fibronectin (FN) adsorption on hydroxyapatite, HA (100) surface at 300K using all-atom MD simulation method. Fibronectin adsorption was found to be governed by the attractive electrostatic interaction, which changed with the electric field strength. Non-monotonous changes in structural integrity of fibronectin were recorded with the change in field strength and direction. This can be attributed to the spatial rearrangement of local charges and global structural changes of the protein. The dipole moment vectors of fibronectin, water and HA quantitatively exhibited similar pattern of orienting themselves parallel to the field direction, with field strength dependent increase in their magnitudes. No significant change has been recorded for radial distribution function of water surrounding fibronectin. Field dependent variation in the salt bridge nets and number of hydrogen bonds between fibronectin and hydroxyapatite were also examined. One of the important results in the context of the cell-material interaction is that the RGD sequence of FN was exposed to solvent side, when the field was applied along a direction outward perpendicular to HA (001) surface. Summarizing, the present study provides quantitative insights into the influence of electric field stimulation on biomolecular interactions involved in fibronectin adsorption on hydroxyapatite surface.

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ADAM10- and presenilin 1/γ-secretase-dependent cleavage of PTPRT mitigates neurodegeneration of Alzheimer’s disease

10.1101/2021.01.11.426157 ◽

2021 ◽

Author(s):

Siling Liu ◽

Zhongyu Zhang ◽

Lianwei Li ◽

Li Yao ◽

Zhanshan Ma ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Synapse Formation ◽

Transmembrane Protein ◽

Synaptic Function ◽

Presenilin 1 ◽

Behavioral Deficits ◽

Altered Gene

AbstractPTPRT (receptor-type tyrosine-protein phosphatase T), as a brain-specific type 1 transmembrane protein, plays an important function in neurodevelopment and synapse formation. Here, we identified that PTPRT is a novel substrate of ADAM10- and presenilin 1/γ-secretase. The intracellular domain (PICD), which was released from the cleavage of PTPRT, translocated to the nucleus and dephosphorylated signal transducer and activator of transcription 3 (pSTAT3Y705). Overexpression of the PICD alone profoundly altered gene expression in neuronal cells. We further found that the downregulation of Ptprt expression was negatively correlated to the accumulation of pSTAT3Y705 in the brains of human Alzheimer’s disease (AD) and model mice. PICD alone not only decreased pSTAT3Y705 and Aβ deposition but also markedly improved synaptic function and behavioral deficits in APP/PS1 mice. Our data demonstrate a distinct role of the ADAM 10- and presenilin 1/γ-secretase-dependent cleavage of PTPRT in mitigating neurodegeneration of Alzheimer’s disease.

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