Journal articles: 'Synaptic proteins loss'

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Reddy, P. Hemachandra, Geethalakshmi Mani, Byung S. Park, Joline Jacques, Geoffrey Murdoch, William Whetsell, Jeffrey Kaye, and Maria Manczak. "Differential loss of synaptic proteins in Alzheimer's disease: Implications for synaptic dysfunction." Journal of Alzheimer's Disease 7, no. 2 (April 18, 2005): 103–17. http://dx.doi.org/10.3233/jad-2005-7203.

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Camporesi, Elena, Johanna Nilsson, Ann Brinkmalm, Bruno Becker, Nicholas J. Ashton, Kaj Blennow, and Henrik Zetterberg. "Fluid Biomarkers for Synaptic Dysfunction and Loss." Biomarker Insights 15 (January 2020): 117727192095031. http://dx.doi.org/10.1177/1177271920950319.

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Synapses are the site for brain communication where information is transmitted between neurons and stored for memory formation. Synaptic degeneration is a global and early pathogenic event in neurodegenerative disorders with reduced levels of pre- and postsynaptic proteins being recognized as a core feature of Alzheimer’s disease (AD) pathophysiology. Together with AD, other neurodegenerative and neurodevelopmental disorders show altered synaptic homeostasis as an important pathogenic event, and due to that, they are commonly referred to as synaptopathies. The exact mechanisms of synapse dysfunction in the different diseases are not well understood and their study would help understanding the pathogenic role of synaptic degeneration, as well as differences and commonalities among them and highlight candidate synaptic biomarkers for specific disorders. The assessment of synaptic proteins in cerebrospinal fluid (CSF), which can reflect synaptic dysfunction in patients with cognitive disorders, is a keen area of interest. Substantial research efforts are now directed toward the investigation of CSF synaptic pathology to improve the diagnosis of neurodegenerative disorders at an early stage as well as to monitor clinical progression. In this review, we will first summarize the pathological events that lead to synapse loss and then discuss the available data on established (eg, neurogranin, SNAP-25, synaptotagmin-1, GAP-43, and α-syn) and emerging (eg, synaptic vesicle glycoprotein 2A and neuronal pentraxins) CSF biomarkers for synapse dysfunction, while highlighting possible utilities, disease specificity, and technical challenges for their detection.

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Xu, Lingyan, Zhiyun Ren, Frances E. Chow, Richard Tsai, Tongzheng Liu, Flavio Rizzolio, Silvia Boffo, et al. "Pathological Role of Peptidyl-Prolyl Isomerase Pin1 in the Disruption of Synaptic Plasticity in Alzheimer’s Disease." Neural Plasticity 2017 (2017): 1–12. http://dx.doi.org/10.1155/2017/3270725.

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Synaptic loss is the structural basis for memory impairment in Alzheimer’s disease (AD). While the underlying pathological mechanism remains elusive, it is known that misfolded proteins accumulate as β-amyloid (Aβ) plaques and hyperphosphorylated Tau tangles decades before the onset of clinical disease. The loss of Pin1 facilitates the formation of these misfolded proteins in AD. Pin1 protein controls cell-cycle progression and determines the fate of proteins by the ubiquitin proteasome system. The activity of the ubiquitin proteasome system directly affects the functional and structural plasticity of the synapse. We localized Pin1 to dendritic rafts and postsynaptic density (PSD) and found the pathological loss of Pin1 within the synapses of AD brain cortical tissues. The loss of Pin1 activity may alter the ubiquitin-regulated modification of PSD proteins and decrease levels of Shank protein, resulting in aberrant synaptic structure. The loss of Pin1 activity, induced by oxidative stress, may also render neurons more susceptible to the toxicity of oligomers of Aβ and to excitation, thereby inhibiting NMDA receptor-mediated synaptic plasticity and exacerbating NMDA receptor-mediated synaptic degeneration. These results suggest that loss of Pin1 activity could lead to the loss of synaptic plasticity in the development of AD.

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Uytterhoeven, Valerie, Sabine Kuenen, Jaroslaw Kasprowicz, Katarzyna Miskiewicz, and Patrik Verstreken. "Loss of Skywalker Reveals Synaptic Endosomes as Sorting Stations for Synaptic Vesicle Proteins." Cell 145, no. 1 (April 2011): 117–32. http://dx.doi.org/10.1016/j.cell.2011.02.039.

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Gulyássy, Péter, Katalin Todorov-Völgyi, Vilmos Tóth, Balázs A. Györffy, Gina Puska, Attila Simor, Gábor Juhász, László Drahos, and Katalin Adrienna Kékesi. "The Effect of Sleep Deprivation and Subsequent Recovery Period on the Synaptic Proteome of Rat Cerebral Cortex." Molecular Neurobiology 59, no. 2 (January 5, 2022): 1301–19. http://dx.doi.org/10.1007/s12035-021-02699-x.

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AbstractSleep deprivation (SD) is commonplace in the modern way of life and has a substantial social, medical, and human cost. Sleep deprivation induces cognitive impairment such as loss of executive attention, working memory decline, poor emotion regulation, increased reaction times, and higher cognitive functions are particularly vulnerable to sleep loss. Furthermore, SD is associated with obesity, diabetes, cardiovascular diseases, cancer, and a vast majority of psychiatric and neurodegenerative disorders are accompanied by sleep disturbances. Despite the widespread scientific interest in the effect of sleep loss on synaptic function, there is a lack of investigation focusing on synaptic transmission on the proteome level. In the present study, we report the effects of SD and recovery period (RP) on the cortical synaptic proteome in rats. Synaptosomes were isolated after 8 h of SD performed by gentle handling and after 16 h of RP. The purity of synaptosome fraction was validated with western blot and electron microscopy, and the protein abundance alterations were analyzed by mass spectrometry. We observed that SD and RP have a wide impact on neurotransmitter-related proteins at both the presynaptic and postsynaptic membranes. The abundance of synaptic proteins has changed to a greater extent in consequence of SD than during RP: we identified 78 proteins with altered abundance after SD and 39 proteins after the course of RP. Levels of most of the altered proteins were upregulated during SD, while RP showed the opposite tendency, and three proteins (Gabbr1, Anks1b, and Decr1) showed abundance changes with opposite direction after SD and RP. The functional cluster analysis revealed that a majority of the altered proteins is related to signal transduction and regulation, synaptic transmission and synaptic assembly, protein and ion transport, and lipid and fatty acid metabolism, while the interaction network analysis revealed several connections between the significantly altered proteins and the molecular processes of synaptic plasticity or sleep. Our proteomic data implies suppression of SNARE-mediated synaptic vesicle exocytosis and impaired endocytic processes after sleep deprivation. Both SD and RP altered GABA neurotransmission and affected protein synthesis, several regulatory processes and signaling pathways, energy homeostatic processes, and metabolic pathways.

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Jadhav, Santosh, Veronika Cubinkova, Ivana Zimova, Veronika Brezovakova, Aladar Madari, Viera Cigankova, and Norbert Zilka. "Tau-mediated synaptic damage in Alzheimer’s disease." Translational Neuroscience 6, no. 1 (January 1, 2015): 214–26. http://dx.doi.org/10.1515/tnsci-2015-0023.

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AbstractSynapses are the principal sites for chemical communication between neurons and are essential for performing the dynamic functions of the brain. In Alzheimer’s disease and related tauopathies, synapses are exposed to disease modified protein tau, which may cause the loss of synaptic contacts that culminate in dementia. In recent decades, structural, transcriptomic and proteomic studies suggest that Alzheimer’s disease represents a synaptic disorder. Tau neurofibrillary pathology and synaptic loss correlate well with cognitive impairment in these disorders. Moreover, regional distribution and the load of neurofibrillary lesions parallel the distribution of the synaptic loss. Several transgenic models of tauopathy expressing various forms of tau protein exhibit structural synaptic deficits. The pathological tau proteins cause the dysregulation of synaptic proteome and lead to the functional abnormalities of synaptic transmission. A large body of evidence suggests that tau protein plays a key role in the synaptic impairment of human tauopathies.

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Bellucci, Arianna, Francesca Longhena, and Maria Grazia Spillantini. "The Role of Rab Proteins in Parkinson’s Disease Synaptopathy." Biomedicines 10, no. 8 (August 10, 2022): 1941. http://dx.doi.org/10.3390/biomedicines10081941.

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In patients affected by Parkinson’s disease (PD), the most common neurodegenerative movement disorder, the brain is characterized by the loss of dopaminergic neurons in the nigrostriatal system, leading to dyshomeostasis of the basal ganglia network activity that is linked to motility dysfunction. PD mostly arises as an age-associated sporadic disease, but several genetic forms also exist. Compelling evidence supports that synaptic damage and dysfunction characterize the very early phases of either sporadic or genetic forms of PD and that this early PD synaptopathy drives retrograde terminal-to-cell body degeneration, culminating in neuronal loss. The Ras-associated binding protein (Rab) family of small GTPases, which is involved in the maintenance of neuronal vesicular trafficking, synaptic architecture and function in the central nervous system, has recently emerged among the major players in PD synaptopathy. In this manuscript, we provide an overview of the main findings supporting the involvement of Rabs in either sporadic or genetic PD pathophysiology, and we highlight how Rab alterations participate in the onset of early synaptic damage and dysfunction.

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Royero, Pedro Xavier, Guilherme Shigueto Vilar Higa, Daiane Soares Kostecki, Bianca Araújo dos Santos, Cayo Almeida, Kézia Accioly Andrade, Erika Reime Kinjo, and Alexandre Hiroaki Kihara. "Ryanodine receptors drive neuronal loss and regulate synaptic proteins during epileptogenesis." Experimental Neurology 327 (May 2020): 113213. http://dx.doi.org/10.1016/j.expneurol.2020.113213.

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Desnos, C., L. Clift-O'Grady, and R. B. Kelly. "Biogenesis of synaptic vesicles in vitro." Journal of Cell Biology 130, no. 5 (September 1, 1995): 1041–49. http://dx.doi.org/10.1083/jcb.130.5.1041.

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Synaptic vesicles are synthesized at a rapid rate in nerve terminals to compensate for their rapid loss during neurotransmitter release. Their biogenesis involves endocytosis of synaptic vesicle membrane proteins from the plasma membrane and requires two steps, the segregation of synaptic vesicle membrane proteins from other cellular proteins, and the packaging of those unique proteins into vesicles of the correct size. By labeling an epitope-tagged variant of a synaptic vesicle protein, VAMP (synaptobrevin), at the cell surface of the neuroendocrine cell line PC12, synaptic vesicle biogenesis could be followed with considerable precision, quantitatively and kinetically. Epitope-tagged VAMP was recovered in synaptic vesicles within a few minutes of leaving the cell surface. More efficient targeting was obtained by using the VAMP mutant, del 61-70. Synaptic vesicles did not form at 15 degrees C although endocytosis still occurred. Synaptic vesicles could be generated in vitro from a homogenate of cells labeled at 15 degrees C. The newly formed vesicles are identical to those formed in vivo in their sedimentation characteristics, the presence of the synaptic vesicle protein synaptophysin, and the absence of detectable transferrin receptor. Brain, but not fibroblast cytosol, allows vesicles of the correct size to form. Vesicle formation is time and temperature-dependent, requires ATP, is calcium independent, and is inhibited by GTP-gamma S. Thus, two key steps in synaptic vesicle biogenesis have been reconstituted in vitro, allowing direct analysis of the proteins involved.

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Ahmad-Annuar, Azlina, Lorenza Ciani, Iordanis Simeonidis, Judit Herreros, Naila Ben Fredj, Silvana B. Rosso, Anita Hall, Stephen Brickley, and Patricia C. Salinas. "Signaling across the synapse: a role for Wnt and Dishevelled in presynaptic assembly and neurotransmitter release." Journal of Cell Biology 174, no. 1 (July 3, 2006): 127–39. http://dx.doi.org/10.1083/jcb.200511054.

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Proper dialogue between presynaptic neurons and their targets is essential for correct synaptic assembly and function. At central synapses, Wnt proteins function as retrograde signals to regulate axon remodeling and the accumulation of presynaptic proteins. Loss of Wnt7a function leads to defects in the localization of presynaptic markers and in the morphology of the presynaptic axons. We show that loss of function of Dishevelled-1 (Dvl1) mimics and enhances the Wnt7a phenotype in the cerebellum. Although active zones appear normal, electrophysiological recordings in cerebellar slices from Wnt7a/Dvl1 double mutant mice reveal a defect in neurotransmitter release at mossy fiber–granule cell synapses. Deficiency in Dvl1 decreases, whereas exposure to Wnt increases, synaptic vesicle recycling in mossy fibers. Dvl increases the number of Bassoon clusters, and like other components of the Wnt pathway, it localizes to synaptic sites. These findings demonstrate that Wnts signal across the synapse on Dvl-expressing presynaptic terminals to regulate synaptic assembly and suggest a potential novel function for Wnts in neurotransmitter release.

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Hayano, Yasufumi, Yugo Ishino, Jung Ho Hyun, Carlos G. Orozco, André Steinecke, Elizabeth Potts, Yasuhiro Oisi, et al. "IgSF11 homophilic adhesion proteins promote layer-specific synaptic assembly of the cortical interneuron subtype." Science Advances 7, no. 29 (July 2021): eabf1600. http://dx.doi.org/10.1126/sciadv.abf1600.

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The most prominent structural hallmark of the mammalian neocortical circuitry is the layer-based organization of specific cell types and synaptic inputs. Accordingly, cortical inhibitory interneurons (INs), which shape local network activity, exhibit subtype-specific laminar specificity of synaptic outputs. However, the underlying molecular mechanisms remain unknown. Here, we demonstrate that Immunoglobulin Superfamily member 11 (IgSF11) homophilic adhesion proteins are preferentially expressed in one of the most distinctive IN subtypes, namely, chandelier cells (ChCs) that specifically innervate axon initial segments of pyramidal neurons (PNs), and their synaptic laminar target. Loss-of-function experiments in either ChCs or postsynaptic cells revealed that IgSF11 is required for ChC synaptic development in the target layer. While overexpression of IgSF11 in ChCs enlarges ChC presynaptic boutons, expressing IgSF11 in nontarget layers induces ectopic ChC synapses. These findings provide evidence that synapse-promoting adhesion proteins, highly localized to synaptic partners, determine the layer-specific synaptic connectivity of the cortical IN subtype.

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Vijayan, Vinoy, and Patrik Verstreken. "Autophagy in the presynaptic compartment in health and disease." Journal of Cell Biology 216, no. 7 (May 17, 2017): 1895–906. http://dx.doi.org/10.1083/jcb.201611113.

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Synapses are functionally distinct neuronal compartments that are critical for brain function, with synaptic dysfunction being an early pathological feature in aging and disease. Given the large number of proteins needed for synaptic function, the proliferation of defective proteins and the subsequent loss of protein homeostasis may be a leading cause of synaptic dysfunction. Autophagic mechanisms are cellular digestion processes that recycle cellular components and contribute to protein homeostasis. Autophagy is important within the nervous system, but its function in specific compartments such as the synapse has been unclear. Evidence from research on both autophagy and synaptic function suggests that there are links between the two and that synaptic homeostasis during aging requires autophagy to regulate protein homeostasis. Exciting new work on autophagy-modulating proteins that are enriched at the synapse has begun to link autophagy to synapses and synaptic dysfunction in disease. A better understanding of these links will help us harness the potential therapeutic benefits of autophagy in combating age-related disorders of the nervous system.

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Davidsson, Pia, and Kaj Blennow. "Neurochemical Dissection of Synaptic Pathology in Alzheimer's Disease." International Psychogeriatrics 10, no. 1 (March 1998): 11–23. http://dx.doi.org/10.1017/s1041610298005110.

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Synaptic pathology has attained increasing attention as being central in the pathogenesis of Alzheimer's disease (AD). To address the question whether synaptic pathology in AD involves the whole synapse, or is limited to specific components thereof, we studied three different synaptic vesicle proteins (rab3a, synaptotagmin, synaptophysin) and also the presynaptic membrane protein GAP-43 and the postsynaptic protein neurogranin. The material included post-mortem brain tissue (frontal cortex, hippocampus, and cerebellum) from 8 patients with early-onset AD (EAD), 11 patients with late-onset AD (LAD), 6 patients with vascular dementia (VAD), and 9 control subjects. A reduction of all synaptic proteins was found in AD, more pronounced in EAD than in LAD, in both the frontal cortex (EAD 30% to 70% vs. LAD 82% to 88% of control value) and hippocampus (EAD 22% to 82% vs. LAD 76% to 89% of control value), whereas only minor changes were found in VAD. The finding that all synaptic proteins were reduced in AD suggests a degeneration and loss of whole synaptic elements that are more pronounced in EAD than in LAD.

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Haq, Naila, Christoph Schmidt-Hieber, Fernando J. Sialana, Lorenza Ciani, Janosch P. Heller, Michelle Stewart, Liz Bentley, et al. "Loss of Bardet-Biedl syndrome proteins causes synaptic aberrations in principal neurons." PLOS Biology 17, no. 9 (September 3, 2019): e3000414. http://dx.doi.org/10.1371/journal.pbio.3000414.

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Bajic, Natasha, Peter Jenner, Clive G. Ballard, and Paul T. Francis. "Proteasome inhibition leads to early loss of synaptic proteins in neuronal culture." Journal of Neural Transmission 119, no. 12 (May 17, 2012): 1467–76. http://dx.doi.org/10.1007/s00702-012-0816-9.

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Mandel, Nicolas, and Nitin Agarwal. "Role of SUMOylation in Neurodegenerative Diseases." Cells 11, no. 21 (October 27, 2022): 3395. http://dx.doi.org/10.3390/cells11213395.

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Neurodegenerative diseases (NDDs) are irreversible, progressive diseases with no effective treatment. The hallmark of NDDs is the aggregation of misfolded, modified proteins, which impair neuronal vulnerability and cause brain damage. The loss of synaptic connection and the progressive loss of neurons result in cognitive defects. Several dysregulated proteins and overlapping molecular mechanisms contribute to the pathophysiology of NDDs. Post-translational modifications (PTMs) are essential regulators of protein function, trafficking, and maintaining neuronal hemostasis. The conjugation of a small ubiquitin-like modifier (SUMO) is a reversible, dynamic PTM required for synaptic and cognitive function. The onset and progression of neurodegenerative diseases are associated with aberrant SUMOylation. In this review, we have summarized the role of SUMOylation in regulating critical proteins involved in the onset and progression of several NDDs.

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Kim, Eunyoung, Lawrence M. Grover, Don Bertolotti, and Todd L. Green. "Growth hormone rescues hippocampal synaptic function after sleep deprivation." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 298, no. 6 (June 2010): R1588—R1596. http://dx.doi.org/10.1152/ajpregu.00580.2009.

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Sleep is required for, and sleep loss impairs, normal hippocampal synaptic N-methyl-d-aspartate (NMDA) glutamate receptor function and expression, hippocampal NMDA receptor-dependent synaptic plasticity, and hippocampal-dependent memory function. Although sleep is essential, the signals linking sleep to hippocampal function are not known. One potential signal is growth hormone. Growth hormone is released during sleep, and its release is suppressed during sleep deprivation. If growth hormone links sleep to hippocampal function, then restoration of growth hormone during sleep deprivation should prevent adverse consequences of sleep loss. To test this hypothesis, we examined rat hippocampus for spontaneous excitatory synaptic currents in CA1 pyramidal neurons, long-term potentiation in area CA1, and NMDA receptor subunit proteins in synaptic membranes. Three days of sleep deprivation caused a significant reduction in NMDA receptor-mediated synaptic currents compared with control treatments. When rats were injected with growth hormone once per day during sleep deprivation, the loss of NMDA receptor-mediated synaptic currents was prevented. Growth hormone injections also prevented the impairment of long-term potentiation that normally follows sleep deprivation. In addition, sleep deprivation led to a selective loss of NMDA receptor 2B (NR2B) from hippocampal synaptic membranes, but normal NR2B expression was restored by growth hormone injection. Our results identify growth hormone as a critical mediator linking sleep to normal synaptic function of the hippocampus.

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Haq, Naila, Christoph Schmidt-Hieber, Fernando J. Sialana, Lorenza Ciani, Janosch P. Heller, Michelle Stewart, Liz Bentley, et al. "Correction: Loss of Bardet-Biedl syndrome proteins causes synaptic aberrations in principal neurons." PLOS Biology 17, no. 10 (October 8, 2019): e3000520. http://dx.doi.org/10.1371/journal.pbio.3000520.

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Mukaetova-Ladinska, E. B., J. Hurt, W. G. Honer, C. R. Harrington, and C. M. Wischik. "Loss of synaptic but not cytoskeletal proteins in the cerebellum of chronic schizophrenics." Neuroscience Letters 317, no. 3 (January 2002): 161–65. http://dx.doi.org/10.1016/s0304-3940(01)02458-2.

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Li, Yingchao, Haitao Yu, Chongyang Chen, Shupeng Li, Zaijun Zhang, Hua Xu, Feiqi Zhu, et al. "Proteomic Profile of Mouse Brain Aging Contributions to Mitochondrial Dysfunction, DNA Oxidative Damage, Loss of Neurotrophic Factor, and Synaptic and Ribosomal Proteins." Oxidative Medicine and Cellular Longevity 2020 (June 9, 2020): 1–21. http://dx.doi.org/10.1155/2020/5408452.

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The deleterious effects of aging on the brain remain to be fully elucidated. In the present study, proteomic changes of young (4-month) and aged (16-month) B6129SF2/J male mouse hippocampus and cerebral cortex were investigated by using nano liquid chromatography tandem mass spectrometry (NanoLC-ESI-MS/MS) combined with tandem mass tag (TMT) labeling technology. Compared with the young animals, 390 hippocampal proteins (121 increased and 269 decreased) and 258 cortical proteins (149 increased and 109 decreased) changed significantly in the aged mouse. Bioinformatic analysis indicated that these proteins are mainly involved in mitochondrial functions (FIS1, DRP1), oxidative stress (PRDX6, GSTP1, and GSTM1), synapses (SYT12, GLUR2), ribosome (RPL4, RPS3), cytoskeletal integrity, transcriptional regulation, and GTPase function. The mitochondrial fission-related proteins FIS1 and DRP1 were significantly increased in the hippocampus and cerebral cortex of the aged mice. Further results in the hippocampus showed that ATP content was significantly reduced in aged mice. A neurotrophin brain-derived neurotrophic factor (BNDF), a protein closely related with synaptic plasticity and memory, was also significantly decreased in the hippocampus of the aged mice, with the tendency of synaptic protein markers including complexin-2, synaptophysin, GLUR2, PSD95, NMDAR2A, and NMDAR1. More interestingly, 8-hydroxydeoxyguanosine (8-OHdG), a marker of DNA oxidative damage, increased as shown by immunofluorescence staining. In summary, we demonstrated that aging is associated with systemic changes involving mitochondrial dysfunction, energy reduction, oxidative stress, loss of neurotrophic factor, synaptic proteins, and ribosomal proteins, as well as molecular deficits involved in various physiological/pathological processes.

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Haberman, Adam, W. Ryan Williamson, Daniel Epstein, Dong Wang, Srisha Rina, Ian A. Meinertzhagen, and P. Robin Hiesinger. "The synaptic vesicle SNARE neuronal Synaptobrevin promotes endolysosomal degradation and prevents neurodegeneration." Journal of Cell Biology 196, no. 2 (January 23, 2012): 261–76. http://dx.doi.org/10.1083/jcb.201108088.

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Soluble NSF attachment protein receptors (SNAREs) are the core proteins in membrane fusion. The neuron-specific synaptic v-SNARE n-syb (neuronal Synaptobrevin) plays a key role during synaptic vesicle exocytosis. In this paper, we report that loss of n-syb caused slow neurodegeneration independent of its role in neurotransmitter release in adult Drosophila melanogaster photoreceptor neurons. In addition to synaptic vesicles, n-Syb localized to endosomal vesicles. Loss of n-syb lead to endosomal accumulations, transmembrane protein degradation defects, and a secondary increase in autophagy. Our evidence suggests a primary defect of impaired delivery of vesicles that contain degradation proteins, including the acidification-activated Cathepsin proteases and the neuron-specific proton pump and V0 adenosine triphosphatase component V100. Overexpressing V100 partially rescued n-syb–dependent degeneration through an acidification-independent endosomal sorting mechanism. Collectively, these findings reveal a role for n-Syb in a neuron-specific sort-and-degrade mechanism that protects neurons from degeneration. Our findings further shed light on which intraneuronal compartments exhibit increased or decreased neurotoxicity.

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Leshchyns’ka, Iryna, and Vladimir Sytnyk. "Synaptic Cell Adhesion Molecules in Alzheimer’s Disease." Neural Plasticity 2016 (2016): 1–9. http://dx.doi.org/10.1155/2016/6427537.

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Alzheimer’s disease (AD) is a neurodegenerative brain disorder associated with the loss of synapses between neurons in the brain. Synaptic cell adhesion molecules are cell surface glycoproteins which are expressed at the synaptic plasma membranes of neurons. These proteins play key roles in formation and maintenance of synapses and regulation of synaptic plasticity. Genetic studies and biochemical analysis of the human brain tissue, cerebrospinal fluid, and sera from AD patients indicate that levels and function of synaptic cell adhesion molecules are affected in AD. Synaptic cell adhesion molecules interact with Aβ, a peptide accumulating in AD brains, which affects their expression and synaptic localization. Synaptic cell adhesion molecules also regulate the production of Aβvia interaction with the key enzymes involved in Aβformation. Aβ-dependent changes in synaptic adhesion affect the function and integrity of synapses suggesting that alterations in synaptic adhesion play key roles in the disruption of neuronal networks in AD.

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Mukaetova-Ladinska, Elizabeta B., Alina Andras, Joan Milne, Zeinab Abdel-All, Iwo Borr, Evelyn Jaros, Robert H. Perry, et al. "Synaptic Proteins and Choline Acetyltransferase Loss in Visual Cortex in Dementia With Lewy Bodies." Journal of Neuropathology & Experimental Neurology 72, no. 1 (January 2013): 53–60. http://dx.doi.org/10.1097/nen.0b013e31827c5710.

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Subhani, Farhan U. "P3-215 Mechanism of synaptic loss, formation of extra proteins & nerve cell death." Neurobiology of Aging 25 (July 2004): S416. http://dx.doi.org/10.1016/s0197-4580(04)81365-4.

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Bajic, Natasha, Peter Jenner, Clive G. Ballard, and Paul T. Francis. "Erratum to: Proteasome inhibition leads to early loss of synaptic proteins in neuronal culture." Journal of Neural Transmission 120, no. 7 (June 5, 2013): 1135. http://dx.doi.org/10.1007/s00702-013-1046-5.

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Dulewicz, Maciej, Agnieszka Kulczyńska-Przybik, Renata Borawska, Agnieszka Słowik, and Barbara Mroczko. "Evaluation of Synaptic and Axonal Dysfunction Biomarkers in Alzheimer’s Disease and Mild Cognitive Impairment Based on CSF and Bioinformatic Analysis." International Journal of Molecular Sciences 23, no. 18 (September 17, 2022): 10867. http://dx.doi.org/10.3390/ijms231810867.

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Synaptic loss and dysfunction are one of the earliest signs of neurodegeneration associated with cognitive decline in Alzheimer’s disease (AD) and other neurodegenerative diseases. This study aimed to assess the relationships between biological processes of the synaptic pathology underlying AD, molecular functions, and dynamics of the change concentrations of selected proteins reflecting synaptic and axonal pathology in dementia stages. Neurogranin (Ng), neuronal pentraxin receptor (NPTXR), and Visinin-like protein 1 (VILIP1) concentrations were measured in the cerebrospinal fluid (CSF) of MCI, AD, and non-demented controls (CTRL) using quantitative immunological methods. Gene ontology (GO) enrichment analysis was used for the functional analysis of tested proteins. The CSF Aβ42/Ng ratio was significantly different between all the compared groups. The CSF NPTXR/Ng ratio was significantly different between MCI compared to CTRL and AD compared to CTRL. The GO enrichment analysis revealed that two terms (the Biological Process (BP) and Cellular Component (CC) levels) are significantly enriched for NPTXR and Ng but not for VILIP1. Both Ng and NPTXR concentrations in CSF are promising synaptic dysfunction biomarkers for the early diagnosis of the disease. Moreover, both proteins are biochemically associated with classical biomarkers and VILIP-1. Mapping shared molecular and biological functions for the tested proteins by GO enrichment analysis may be beneficial in screening and setting new research targets.

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Tang, Bin, Tingting Wang, Huida Wan, Li Han, Xiaoyan Qin, Yaoyang Zhang, Jian Wang, et al. "Fmr1 deficiency promotes age-dependent alterations in the cortical synaptic proteome." Proceedings of the National Academy of Sciences 112, no. 34 (August 11, 2015): E4697—E4706. http://dx.doi.org/10.1073/pnas.1502258112.

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Fragile X syndrome (FXS) is an X-linked neurodevelopmental disorder characterized by severe intellectual disability and other symptoms including autism. Although caused by the silencing of a single gene, Fmr1 (fragile X mental retardation 1), the complexity of FXS pathogenesis is amplified because the encoded protein, FMRP, regulates the activity-dependent translation of numerous mRNAs. Although the mRNAs that associate with FMRP have been extensively studied, little is known regarding the proteins whose expression levels are altered, directly or indirectly, by loss of FMRP during brain development. Here we systematically measured protein expression in neocortical synaptic fractions from Fmr1 knockout (KO) and wild-type (WT) mice at both adolescent and adult stages. Although hundreds of proteins are up-regulated in the absence of FMRP in young mice, this up-regulation is largely diminished in adulthood. Up-regulated proteins included previously unidentified as well as known targets involved in synapse formation and function and brain development and others linked to intellectual disability and autism. Comparison with putative FMRP target mRNAs and autism susceptibility genes revealed substantial overlap, consistent with the idea that the autism endophenotype of FXS is due to a “multiple hit” effect of FMRP loss, particularly within the PSD95 interactome. Through studies of de novo protein synthesis in primary cortical neurons from KO and WT mice, we found that neurons lacking FMRP produce nascent proteins at higher rates, many of which are synaptic proteins and encoded by FMRP target mRNAs. Our results provide a greatly expanded view of protein changes in FXS and identify age-dependent effects of FMRP in shaping the neuronal proteome.

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Carmona, Asuncion, Stéphane Roudeau, and Richard Ortega. "Molecular Mechanisms of Environmental Metal Neurotoxicity: A Focus on the Interactions of Metals with Synapse Structure and Function." Toxics 9, no. 9 (August 27, 2021): 198. http://dx.doi.org/10.3390/toxics9090198.

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Environmental exposure to neurotoxic metals and metalloids such as arsenic, cadmium, lead, mercury, or manganese is a global health concern affecting millions of people worldwide. Depending on the period of exposure over a lifetime, environmental metals can alter neurodevelopment, neurobehavior, and cognition and cause neurodegeneration. There is increasing evidence linking environmental exposure to metal contaminants to the etiology of neurological diseases in early life (e.g., autism spectrum disorder) or late life (e.g., Alzheimer’s disease). The known main molecular mechanisms of metal-induced toxicity in cells are the generation of reactive oxygen species, the interaction with sulfhydryl chemical groups in proteins (e.g., cysteine), and the competition of toxic metals with binding sites of essential metals (e.g., Fe, Cu, Zn). In neurons, these molecular interactions can alter the functions of neurotransmitter receptors, the cytoskeleton and scaffolding synaptic proteins, thereby disrupting synaptic structure and function. Loss of synaptic connectivity may precede more drastic alterations such as neurodegeneration. In this article, we will review the molecular mechanisms of metal-induced synaptic neurotoxicity.

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Liao, Lujian, Sung Kyu Park, Tao Xu, Peter Vanderklish, and John R. Yates. "Quantitative proteomic analysis of primary neurons reveals diverse changes in synaptic protein content in fmr1 knockout mice." Proceedings of the National Academy of Sciences 105, no. 40 (September 30, 2008): 15281–86. http://dx.doi.org/10.1073/pnas.0804678105.

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Fragile X syndrome (FXS) is a common inherited form of mental retardation that is caused, in the vast majority of cases, by the transcriptional silencing of a single gene, fmr1. The encoded protein, FMRP, regulates mRNA translation in neuronal dendrites, and it is thought that changes in translation-dependent forms of synaptic plasticity lead to many symptoms of FXS. However, little is known about the potentially extensive changes in synaptic protein content that accompany loss of FMRP. Here, we describe the development of a high-throughput quantitative proteomic method to identify differences in synaptic protein expression between wild-type and fmr1−/− mouse cortical neurons. The method is based on stable isotope labeling by amino acids in cell culture (SILAC), which has been used to characterize differentially expressed proteins in dividing cells, but not in terminally differentiated cells because of reduced labeling efficiency. To address the issue of incomplete labeling, we developed a mathematical method to normalize protein ratios relative to a reference based on the labeling efficiency. Using this approach, in conjunction with multidimensional protein identification technology (MudPIT), we identified >100 proteins that are up- or down-regulated. These proteins fall into a variety of functional categories, including those regulating synaptic structure, neurotransmission, dendritic mRNA transport, and several proteins implicated in epilepsy and autism, two endophenotypes of FXS. These studies provide insights into the potential origins of synaptic abnormalities in FXS and a demonstration of a methodology that can be used to explore neuronal protein changes in neurological disorders.

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Wong, Man Yan, Changliang Liu, Shan Shan H. Wang, Aram C. F. Roquas, Stephen C. Fowler, and Pascal S. Kaeser. "Liprin-α3 controls vesicle docking and exocytosis at the active zone of hippocampal synapses." Proceedings of the National Academy of Sciences 115, no. 9 (February 8, 2018): 2234–39. http://dx.doi.org/10.1073/pnas.1719012115.

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The presynaptic active zone provides sites for vesicle docking and release at central nervous synapses and is essential for speed and accuracy of synaptic transmission. Liprin-α binds to several active zone proteins, and loss-of-function studies in invertebrates established important roles for Liprin-α in neurodevelopment and active zone assembly. However, Liprin-α localization and functions in vertebrates have remained unclear. We used stimulated emission depletion superresolution microscopy to systematically determine the localization of Liprin-α2 and Liprin-α3, the two predominant Liprin-α proteins in the vertebrate brain, relative to other active-zone proteins. Both proteins were widely distributed in hippocampal nerve terminals, and Liprin-α3, but not Liprin-α2, had a prominent component that colocalized with the active-zone proteins Bassoon, RIM, Munc13, RIM-BP, and ELKS. To assess Liprin-α3 functions, we generated Liprin-α3–KO mice by using CRISPR/Cas9 gene editing. We found reduced synaptic vesicle tethering and docking in hippocampal neurons of Liprin-α3–KO mice, and synaptic vesicle exocytosis was impaired. Liprin-α3 KO also led to mild alterations in active zone structure, accompanied by translocation of Liprin-α2 to active zones. These findings establish important roles for Liprin-α3 in active-zone assembly and function, and suggest that interplay between various Liprin-α proteins controls their active-zone localization.

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Mukaetova-Ladinska, Elizabeta B., John H. Xuereb, Francisco Garcia-Sierra, Jenny Hurt, Herman-J. Gertz, Richard Hills, Carol Brayne, et al. "Lewy Body Variant of Alzheimer's Disease: Selective Neocortical Loss of t-SNARE Proteins and Loss of MAP2 and α-Synuclein in Medial Temporal Lobe." Scientific World JOURNAL 9 (2009): 1463–75. http://dx.doi.org/10.1100/tsw.2009.151.

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Lewy bodies (LBs) appear in the brains of nondemented individuals and also occur in a range of neurodegenerative disorders, such as dementia with Lewy bodies (DLB) and Parkinson's disease. A number of people with a definite diagnosis of Alzheimer's disease (AD) also exhibit these intraneuronal inclusions in allo- and/or neocortical areas. The latter, referred to as Lewy body variant of AD (LBV), bears a clinical resemblance to AD in terms of age at onset, duration of illness, cognitive impairment, and illness severity. Since the presence of LBs is accompanied by neuronal cytoskeleton changes, it is possible that the latter may influence neuronal connectivity via alterations to the synaptic network. To address this, we examined the expression of synaptic proteins (synaptophysin, syntaxin, SNAP-25, and α-synuclein) and two cytoskeletal proteins (tau and MAP2) in the brain tissue of subjects enrolled in a population-based autopsy study (n = 47). They were divided into groups with no memory problems (control group, n = 15), LBV (n = 5), AD devoid of LBs (n = 17), cerebrovascular dementia (n = 3), and mixed dementia (n = 7). The LBV and AD groups had a similar degree of cognitive impairment and neuropathological staging in terms of Braak staging and CERAD score. In comparison with the control group and the dementia groups without LBs, the LBV group had significantly lower levels of syntaxin and SNAP-25 (23%) in the neocortex, and depletion of MAP2 (64%), SNAP-25 (34%), and α-synuclein (44%) proteins in the medial temporal lobes. These findings suggest that the t-SNARE complex deficit present in LBV may be associated with the presence of LB-related pathology and may explain the more profound cholinergic loss seen in these patients.

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Han, Ying, Le Chen, Jingyun Liu, Jie Chen, Chunyang Wang, Yu Guo, Xuebin Yu, Chenghong Zhang, Haiying Chu, and Haiying Ma. "A Class I HDAC Inhibitor Rescues Synaptic Damage and Neuron Loss in APP-Transfected Cells and APP/PS1 Mice through the GRIP1/AMPA Pathway." Molecules 27, no. 13 (June 29, 2022): 4160. http://dx.doi.org/10.3390/molecules27134160.

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As a neurodegenerative disease, Alzheimer’s disease (AD) seriously affects the health of older people. Changes in synapses occur first over the course of the disease, perhaps even before the formation of Aβ plaques. Histone deacetylase (HDAC) mediates the damage of Aβ oligomers to dendritic spines. Therefore, we examined the relationship between HDAC activity and synaptic defects using an HDAC inhibitor (HDACI), BG45, in the human neuroblastoma SH-SY5Y cell line with stable overexpression of Swedish mutant APP (APPsw) and in APP/PS1 transgenic mice during this study. The cells were treated with 15 μM BG45 and the APP/PS1 mice were treated with 30 mg/kg BG45. We detected the levels of synapse-related proteins, HDACs, tau phosphorylation, and amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors using Western blotting and immunohistochemistry. We also measured the expression of cytoskeletal proteins in the cell model. The mRNA levels of the glutamate ion receptor alginate subunit 2 (GRIK2), sodium voltage-gated channel beta subunit (SCN3B), synaptophysin (SYP), Grm2 (the gene encoding glutamate receptor subunit 2 (GluR2)), Grid2IP, glutamate receptor interacting protein 1 (GRIP1), and GRIP2 were detected to explore the effects of the HDACI on regulating the expression of synaptic proteins and AMPA receptors. According to our studies, the expressions of HDAC1, HDAC2, and HDAC3 were increased, which were accompanied by the downregulation of the synapse-related proteins SYP, postsynaptic dendritic protein (PSD-95), and spinophilin as early as 24 h after transfection with the APPsw gene. BG45 upregulated the expression of synapse-related proteins and repaired cytoskeletal damage. In vivo, BG45 alleviated the apoptosis-mediated loss of hippocampal neurons, upregulated synapse-related proteins, reduced Aβ deposition and phosphorylation of tau, and increased the levels of the synapse-related genes GRIK2, SCN3B, SYP, Grm2, and Grid2IP. BG45 increased the expression of the AMPA receptor subunits GluA1, GluA2, and GluA3 on APPsw-transfected cells and increased GRIP1 and GRIP2 expression and AMPA receptor phosphorylation in vivo. Based on these results, HDACs are involved in the early process of synaptic defects in AD models, and BG45 may rescue synaptic damage and the loss of hippocampal neurons by specifically inhibiting HDAC1, HDAC2, and HDAC3, thereby modulating AMPA receptor transduction, increasing synapse-related gene expression, and finally enhancing the function of excitatory synapses. BG45 may be considered a potential drug for the treatment of early AD in further studies.

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Tran, Phu V., Srikanth Dakoji, Kathryn H. Reise, Kathleen K. Storey, and Michael K. Georgieff. "Fetal iron deficiency alters the proteome of adult rat hippocampal synaptosomes." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 305, no. 11 (December 1, 2013): R1297—R1306. http://dx.doi.org/10.1152/ajpregu.00292.2013.

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Fetal and neonatal iron deficiency results in cognitive impairments in adulthood despite prompt postnatal iron replenishment. To systematically determine whether abnormal expression and localization of proteins that regulate adult synaptic efficacy are involved, we used a quantitative proteomic approach (isobaric tags for relative and absolute quantitation, iTRAQ) and pathway analysis to identify dysregulated proteins in hippocampal synapses of fetal iron deficiency model. Rat pups were made iron deficient (ID) from gestational day 2 through postnatal day (P) 7 by providing pregnant and nursing dams an ID diet (4 ppm Fe) after which they were rescued with an iron-sufficient diet (200 ppm Fe). This paradigm resulted in a 40% loss of brain iron at P15 with complete recovery by P56. Synaptosomes were prepared from hippocampi of the formerly iron-deficient (FID) and always iron-sufficient controls rats at P65 using a sucrose gradient method. Six replicates per group that underwent iTRAQ labeling and LC-MS/MS analysis for protein identification and comparison elucidated 331 differentially expressed proteins. Western analysis was used to confirm findings for selected proteins in the glutamate receptor signaling pathway, which regulates hippocampal synaptic plasticity, a cellular process critical for learning and memory. Bioinformatics were performed using knowledge-based Interactive Pathway Analysis. FID synaptosomes show altered expression of synaptic proteins-mediated cellular signalings, supporting persistent impacts of fetal iron deficiency on synaptic efficacy, which likely cause the cognitive dysfunction and neurobehavioral abnormalities. Importantly, the findings uncover previously unsuspected pathways, including neuronal nitric oxide synthase signaling, identifying additional mechanisms that may contribute to the long-term biobehavioral deficits.

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Ju, In Gyoung, Namkwon Kim, Jin Gyu Choi, Jong Kil Lee, and Myung Sook Oh. "Cuscutae Japonicae Semen Ameliorates Memory Dysfunction by Rescuing Synaptic Damage in Alzheimer’s Disease Models." Nutrients 11, no. 11 (October 28, 2019): 2591. http://dx.doi.org/10.3390/nu11112591.

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Alzheimer’s disease (AD) is the most common type of dementia in the elderly. It is characterized by the accumulation of amyloid-beta (Aβ) and progressive cognitive impairment. To alleviate the symptoms of AD, functional foods and nutrients have been used for centuries. In this study, we investigated whether Cuscutae Japonicae Semen (CJS), a medicinal food traditionally used in East Asia, has effects on memory improvement and synapse protection in AD. We orally administered CJS to 5x familiar AD (5xFAD) transgenic mice and performed the Morris water maze test. The results showed that CJS treatment ameliorated the decline of memory function. Then, we demonstrated that CJS attenuated the degeneration of pre- and post-synaptic proteins in the hippocampi of 5xFAD mice. To demonstrate the effects of CJS in vitro, we treated Aβ in primary neuronal culture with CJS and observed that CJS rescued the loss of functional synapses. The protective effects of CJS on the synapse were due to the inhibition of activated caspase-3 expression. Additionally, CJS inhibited the phosphorylation of glycogen synthase kinase-3β and tau proteins, which contribute to synaptic dysfunction. Taken together, our results suggest that CJS is efficient in alleviating memory loss by rescuing caspase-3-mediated synaptic damage in AD treatment.

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Pintana, Hiranya, Nattayaporn Apaijai, Sasiwan Kerdphoo, Wasana Pratchayasakul, Jirapas Sripetchwandee, Panan Suntornsaratoon, Narattaphol Charoenphandhu, Nipon Chattipakorn, and Siriporn C. Chattipakorn. "Hyperglycemia induced the Alzheimer’s proteins and promoted loss of synaptic proteins in advanced-age female Goto-Kakizaki (GK) rats." Neuroscience Letters 655 (August 2017): 41–45. http://dx.doi.org/10.1016/j.neulet.2017.06.041.

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Stevens-Bullmore, Hamish, Don Kulasiri, and Sandhya Samarasinghe. "A Modeling and Analysis Study Reveals That CaMKII in Synaptic Plasticity Is a Dominant Affecter in CaM Systems in a T286 Phosphorylation-Dependent Manner." Molecules 27, no. 18 (September 14, 2022): 5974. http://dx.doi.org/10.3390/molecules27185974.

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NMDAR-dependent synaptic plasticity in the hippocampus consists of two opposing forces: long-term potentiation (LTP), which strengthens synapses and long-term depression (LTD), which weakens synapses. LTP and LTD are associated with memory formation and loss, respectively. Synaptic plasticity is controlled at a molecular level by Ca2+-mediated protein signaling. Here, Ca2+ binds the protein, calmodulin (CaM), which modulates synaptic plasticity in both directions. This is because Ca2+-bound CaM activates both LTD-and LTP-inducing proteins. Understanding how CaM responds to Ca2+ signaling and how this translates into synaptic plasticity is therefore important to understanding synaptic plasticity induction. In this paper, CaM activation by Ca2+ and calmodulin binding to downstream proteins was mathematically modeled using differential equations. Simulations were monitored with and without theoretical knockouts and, global sensitivity analyses were performed to determine how Ca2+/CaM signaling occurred at various Ca2+ signals when CaM levels were limiting. At elevated stimulations, the total CaM pool rapidly bound to its protein binding targets which regulate both LTP and LTD. This was followed by CaM becoming redistributed from low-affinity to high-affinity binding targets. Specifically, CaM was redistributed away from LTD-inducing proteins to bind the high-affinity LTP-inducing protein, calmodulin-dependent kinase II (CaMKII). In this way, CaMKII acted as a dominant affecter and repressed activation of opposing CaM-binding protein targets. The model thereby showed a novel form of CaM signaling by which the two opposing pathways crosstalk indirectly. The model also found that CaMKII can repress cAMP production by repressing CaM-regulated proteins, which catalyze cAMP production. The model also found that at low Ca2+ stimulation levels, typical of LTD induction, CaM signaling was unstable and is therefore unlikely to alone be enough to induce synaptic depression. Overall, this paper demonstrates how limiting levels of CaM may be a fundamental aspect of Ca2+ regulated signaling which allows crosstalk among proteins without requiring directly interaction.

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Dulewicz, Maciej, Agnieszka Kulczyńska-Przybik, Agnieszka Słowik, Renata Borawska, and Barbara Mroczko. "Neurogranin and Neuronal Pentraxin Receptor as Synaptic Dysfunction Biomarkers in Alzheimer’s Disease." Journal of Clinical Medicine 10, no. 19 (October 2, 2021): 4575. http://dx.doi.org/10.3390/jcm10194575.

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Synaptic loss and dysfunction are one of the earliest signs of neurodegeneration associated with cognitive decline in Alzheimer’s disease (AD). It seems that by assessing proteins related to synapses, one may reflect their dysfunction and improve the understanding of neurobiological processes in the early stage of the disease. To our best knowledge, this is the first study that analyzes the CSF concentrations of two synaptic proteins together, such as neurogranin (Ng) and neuronal pentraxins receptor (NPTXR) in relation to neurochemical dementia biomarkers in Alzheimer’s disease. Methods: Ng, NPTXR and classical AD biomarkers concentrations were measured in the CSF of patients with AD and non-demented controls (CTRL) using an enzyme-linked immunosorbent assay (ELISA) and Luminex xMAP technology. Results: The CSF level of Ng was significantly higher, whereas the NPTXR was significantly lower in the AD patients than in cognitively healthy controls. As a first, we calculated the NPTXR/Ng ratio as an indicator of synaptic disturbance. The patients with AD presented a significantly decreased NPTXR/Ng ratio. The correlation was observed between both proteins in the AD and the whole study group. Furthermore, the relationship between the Ng level and pTau181 was found in the AD group of patients. Conclusions: The Ng and NPTXR concentrations in CSF are promising synaptic dysfunction biomarkers reflecting pathological changes in AD.

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Becker, Guillaume, Sylvestre Dammicco, Mohamed Ali Bahri, and Eric Salmon. "The Rise of Synaptic Density PET Imaging." Molecules 25, no. 10 (May 14, 2020): 2303. http://dx.doi.org/10.3390/molecules25102303.

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Many neurological disorders are related to synaptic loss or pathologies. Before the boom of positrons emission tomography (PET) imaging of synapses, synaptic quantification could only be achieved in vitro on brain samples after autopsy or surgical resections. Until the mid-2010s, electron microscopy and immunohistochemical labelling of synaptic proteins were the gold-standard methods for such analyses. Over the last decade, several PET radiotracers for the synaptic vesicle 2A protein have been developed to achieve in vivo synapses visualization and quantification. Different strategies were used, namely radiolabelling with either 11C or 18F, preclinical development in rodent and non-human primates, and binding quantification with different kinetic modelling methods. This review provides an overview of these PET tracers and underlines their perspectives and limitations by focusing on radiochemical aspects, as well as preclinical proof-of-concept and the main clinical outcomes described so far.

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Dagar, Sushma, Saumya Nagar, Manvi Goel, Pitchaiah Cherukuri, and Narender K. Dhingra. "Loss of Photoreceptors Results in Upregulation of Synaptic Proteins in Bipolar Cells and Amacrine Cells." PLoS ONE 9, no. 3 (March 4, 2014): e90250. http://dx.doi.org/10.1371/journal.pone.0090250.

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Repicky, Sarah, and Kendal Broadie. "Metabotropic Glutamate Receptor–Mediated Use–Dependent Down-Regulation of Synaptic Excitability Involves the Fragile X Mental Retardation Protein." Journal of Neurophysiology 101, no. 2 (February 2009): 672–87. http://dx.doi.org/10.1152/jn.90953.2008.

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Loss of the mRNA-binding protein FMRP results in the most common inherited form of both mental retardation and autism spectrum disorders: fragile X syndrome (FXS). The leading FXS hypothesis proposes that metabotropic glutamate receptor (mGluR) signaling at the synapse controls FMRP function in the regulation of local protein translation to modulate synaptic transmission strength. In this study, we use the Drosophila FXS disease model to test the relationship between Drosophila FMRP (dFMRP) and the sole Drosophila mGluR (dmGluRA) in regulation of synaptic function, using two-electrode voltage-clamp recording at the glutamatergic neuromuscular junction (NMJ). Null dmGluRA mutants show minimal changes in basal synapse properties but pronounced defects during sustained high-frequency stimulation (HFS). The double null dfmr1;dmGluRA mutant shows repression of enhanced augmentation and delayed onset of premature long-term facilitation (LTF) and strongly reduces grossly elevated post-tetanic potentiation (PTP) phenotypes present in dmGluRA-null animals. Null dfmr1 mutants show features of synaptic hyperexcitability, including multiple transmission events in response to a single stimulus and cyclic modulation of transmission amplitude during prolonged HFS. The double null dfmr1;dmGluRA mutant shows amelioration of these defects but does not fully restore wildtype properties in dfmr1-null animals. These data suggest that dmGluRA functions in a negative feedback loop in which excess glutamate released during high-frequency transmission binds the glutamate receptor to dampen synaptic excitability, and dFMRP functions to suppress the translation of proteins regulating this synaptic excitability. Removal of the translational regulator partially compensates for loss of the receptor and, similarly, loss of the receptor weakly compensates for loss of the translational regulator.

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Park, Esther, Anthony G. Lau, Kristin L. Arendt, and Lu Chen. "FMRP Interacts with RARα in Synaptic Retinoic Acid Signaling and Homeostatic Synaptic Plasticity." International Journal of Molecular Sciences 22, no. 12 (June 19, 2021): 6579. http://dx.doi.org/10.3390/ijms22126579.

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The fragile X syndrome (FXS) is an X-chromosome-linked neurodevelopmental disorder with severe intellectual disability caused by inactivation of the fragile X mental retardation 1 (FMR1) gene and subsequent loss of the fragile X mental retardation protein (FMRP). Among the various types of abnormal synaptic function and synaptic plasticity phenotypes reported in FXS animal models, defective synaptic retinoic acid (RA) signaling and subsequent defective homeostatic plasticity have emerged as a major synaptic dysfunction. However, the mechanism underlying the defective synaptic RA signaling in the absence of FMRP is unknown. Here, we show that RARα, the RA receptor critically involved in synaptic RA signaling, directly interacts with FMRP. This interaction is enhanced in the presence of RA. Blocking the interaction between FMRP and RARα with a small peptide corresponding to the critical binding site in RARα abolishes RA-induced increases in excitatory synaptic transmission, recapitulating the phenotype seen in the Fmr1 knockout mouse. Taken together, these data suggest that not only are functional FMRP and RARα necessary for RA-dependent homeostatic synaptic plasticity, but that the interaction between these two proteins is essential for proper transcription-independent RA signaling. Our results may provide further mechanistic understanding into FXS synaptic pathophysiology.

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García-Cáceres, Cristina, Esther Fuente-Martín, Emma Burgos-Ramos, Miriam Granado, Laura M. Frago, Vicente Barrios, Tamas Horvath, Jesús Argente, and Julie A. Chowen. "Differential Acute and Chronic Effects of Leptin on Hypothalamic Astrocyte Morphology and Synaptic Protein Levels." Endocrinology 152, no. 5 (February 22, 2011): 1809–18. http://dx.doi.org/10.1210/en.2010-1252.

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Astrocytes participate in neuroendocrine functions partially through modulation of synaptic input density in the hypothalamus. Indeed, glial ensheathing of neurons is modified by specific hormones, thus determining the availability of neuronal membrane space for synaptic inputs, with the loss of this plasticity possibly being involved in pathological processes. Leptin modulates synaptic inputs in the hypothalamus, but whether astrocytes participate in this action is unknown. Here we report that astrocyte structural proteins, such as glial fibrillary acidic protein (GFAP) and vimentin, are induced and astrocyte morphology modified by chronic leptin administration (intracerebroventricular, 2 wk), with these changes being inversely related to modifications in synaptic protein densities. Similar changes in glial structural proteins were observed in adult male rats that had increased body weight and circulating leptin levels due to neonatal overnutrition (overnutrition: four pups/litter vs. control: 12 pups/litter). However, acute leptin treatment reduced hypothalamic GFAP levels and induced synaptic protein levels 1 h after administration, with no effect on vimentin. In primary hypothalamic astrocyte cultures leptin also reduced GFAP levels at 1 h, with an induction at 24 h, indicating a possible direct effect of leptin. Hence, one mechanism by which leptin may affect metabolism is by modifying hypothalamic astrocyte morphology, which in turn could alter synaptic inputs to hypothalamic neurons. Furthermore, the responses to acute and chronic leptin exposure are inverse, raising the possibility that increased glial activation in response to chronic leptin exposure could be involved in central leptin resistance.

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Albrecht, Jan, and Magdalena Zielińska. "Deficit of astroglia-derived thrombospondin-1 and loss of synaptic proteins in hepatic encephalopathy: do ammonia-overexposed astrocytes derange the synaptic hardware?" Journal of Neurochemistry 131, no. 3 (August 8, 2014): 265–67. http://dx.doi.org/10.1111/jnc.12823.

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Gu, Mingyu, Kim Schuske, Shigeki Watanabe, Qiang Liu, Paul Baum, Gian Garriga, and Erik M. Jorgensen. "μ2 adaptin facilitates but is not essential for synaptic vesicle recycling in Caenorhabditis elegans." Journal of Cell Biology 183, no. 5 (December 1, 2008): 881–92. http://dx.doi.org/10.1083/jcb.200806088.

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Synaptic vesicles must be recycled to sustain neurotransmission, in large part via clathrin-mediated endocytosis. Clathrin is recruited to endocytic sites on the plasma membrane by the AP2 adaptor complex. The medium subunit (μ2) of AP2 binds to cargo proteins and phosphatidylinositol-4,5-bisphosphate on the cell surface. Here, we characterize the apm-2 gene (also called dpy-23), which encodes the only μ2 subunit in the nematode Caenorhabditis elegans. APM-2 is highly expressed in the nervous system and is localized to synapses; yet specific loss of APM-2 in neurons does not affect locomotion. In apm-2 mutants, clathrin is mislocalized at synapses, and synaptic vesicle numbers and evoked responses are reduced to 60 and 65%, respectively. Collectively, these data suggest AP2 μ2 facilitates but is not essential for synaptic vesicle recycling.

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Bhat, Mujtaba Aamir, Khurshid Ahmad, Mohd Sajjad Ahmad Khan, Mudasir Ahmad Bhat, Ahmad Almatroudi, Safikur Rahman, and Arif Tasleem Jan. "Expedition into Taurine Biology: Structural Insights and Therapeutic Perspective of Taurine in Neurodegenerative Diseases." Biomolecules 10, no. 6 (June 5, 2020): 863. http://dx.doi.org/10.3390/biom10060863.

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Neurodegenerative diseases (NDs) are characterized by the accumulation of misfolded proteins. The hallmarks of protein aggregation in NDs proceed with impairment in the mitochondrial function, besides causing an enhancement in endoplasmic reticulum (ER) stress, neuroinflammation and synaptic loss. As accumulation of misfolded proteins hampers normal neuronal functions, it triggers ER stress, which leads to the activation of downstream effectors formulating events along the signaling cascade—referred to as unfolded protein response (UPRER) —thereby controlling cellular gene expression. The absence of disease-modifying therapeutic targets in different NDs, and the exponential increase in the number of cases, makes it critical to explore new approaches to treating these devastating diseases. In one such approach, osmolytes (low molecular weight substances), such as taurine have been found to promote protein folding under stress conditions, thereby averting aggregation of the misfolded proteins. Maintaining the structural integrity of the protein, taurine-mediated resumption of protein folding prompts a shift in folding homeostasis more towards functionality than towards aggregation and degradation. Together, taurine enacts protection in NDs by causing misfolded proteins to refold, so as to regain their stability and functionality. The present study provides recent and useful insights into understanding the progression of NDs, besides summarizing the genetics of NDs in correlation with mitochondrial dysfunction, ER stress, neuroinflammation and synaptic loss. It also highlights the structural and functional aspects of taurine in imparting protection against the aggregation/misfolding of proteins, thereby shifting the focus more towards the development of effective therapeutic modules that could avert the development of NDs.

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Lee, Jin-Sook, Won Jin Cho, Leah Shin, and Bhanu P. Jena. "Involvement of cholesterol in synaptic vesicle swelling." Experimental Biology and Medicine 235, no. 4 (April 2010): 470–77. http://dx.doi.org/10.1258/ebm.2010.009259.

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Studies demonstrate that cholesterol plays a critical role in the regulation of neurotransmitter release and that secretory vesicle swelling is a requirement for the regulated expulsion of intravesicular contents during cell secretion. In view of this, the involvement of cholesterol in synaptic vesicle swelling was hypothesized and tested in the present study, using isolated synaptic vesicles from rat brain and the determination of their swelling competency in the presence and absence of cholesterol. The involvement of the water channel aquaporin-6 (AQP-6) and proton pump vH+-ATPase in GTP-G αo-mediated synaptic vesicle swelling has been reported previously. Mastoparan, the amphiphilic tetradecapeptide from wasp venom, known to activate the GTPase activity of G αo/i proteins, stimulates synaptic vesicle swelling in the presence of GTP. In the current study, using nanometer-scale precision measurements of isolated synaptic vesicles, we report for the first time that depletion of cholesterol from synaptic vesicle membrane results in a significant loss of GTP-mastoparan-stimulable synaptic vesicle swelling. In contrast, incorporation of cholesterol into the synaptic vesicle membrane potentiates GTP-mastoparan-stimulable vesicle swelling. Our study further demonstrates that this effect of cholesterol is due, in part, to its involvement in the interactions between AQP-6, vH+-ATPase and the GTP-binding G αo protein at the synaptic vesicle membrane.

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Senatore, Assunta, Elena Restelli, and Roberto Chiesa. "Synaptic Dysfunction in Prion Diseases: A Trafficking Problem?" International Journal of Cell Biology 2013 (2013): 1–15. http://dx.doi.org/10.1155/2013/543803.

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Synaptic dysfunction is an important cause of neurological symptoms in prion diseases, a class of clinically heterogeneous neurodegenerative disorders caused by misfolding of the cellular prion protein (PrPC). Experimental data suggest that accumulation of misfoldedPrPCin the endoplasmic reticulum (ER) may be crucial in synaptic failure, possibly because of the activation of the translational repression pathway of the unfolded protein response. Here, we report that this pathway is not operative in mouse models of genetic prion disease, consistent with our previous observation that ER stress is not involved. Building on our recent finding that ER retention of mutantPrPCimpairs the secretory trafficking of calcium channels essential for synaptic function, we propose a model of pathogenicity in which intracellular retention of misfoldedPrPCresults in loss of function or gain of toxicity ofPrPC-interacting proteins. This neurotoxic modality may also explain the phenotypic heterogeneity of prion diseases.

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Deliu, Lisa Patricia, Michael Turingan, Deeshpaul Jadir, Byoungchun Lee, Abhishek Ghosh, and Savraj Singh Grewal. "Serotonergic neuron ribosomal proteins regulate the neuroendocrine control of Drosophila development." PLOS Genetics 18, no. 9 (September 1, 2022): e1010371. http://dx.doi.org/10.1371/journal.pgen.1010371.

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The regulation of ribosome function is a conserved mechanism of growth control. While studies in single cell systems have defined how ribosomes contribute to cell growth, the mechanisms that link ribosome function to organismal growth are less clear. Here we explore this issue using Drosophila Minutes, a class of heterozygous mutants for ribosomal proteins. These animals exhibit a delay in larval development caused by decreased production of the steroid hormone ecdysone, the main regulator of larval maturation. We found that this developmental delay is not caused by decreases in either global ribosome numbers or translation rates. Instead, we show that they are due in part to loss of Rp function specifically in a subset of serotonin (5-HT) neurons that innervate the prothoracic gland to control ecdysone production. We find that these effects do not occur due to altered protein synthesis or proteostasis, but that Minute animals have reduced expression of synaptotagmin, a synaptic vesicle protein, and that the Minute developmental delay can be partially reversed by overexpression of synaptic vesicle proteins in 5-HTergic cells. These results identify a 5-HT cell-specific role for ribosomal function in the neuroendocrine control of animal growth and development.

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Tannenberg, Rudi K., Heather L. Scott, Anthony E. G. Tannenberg, and Peter R. Dodd. "Selective loss of synaptic proteins in Alzheimer's disease: Evidence for an increased severity with APOE ɛ4." Neurochemistry International 49, no. 7 (December 2006): 631–39. http://dx.doi.org/10.1016/j.neuint.2006.05.004.

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Plum, Sarah, Britta Eggers, Stefan Helling, Markus Stepath, Carsten Theiss, Renata E. P. Leite, Mariana Molina, et al. "Proteomic Characterization of Synaptosomes from Human Substantia Nigra Indicates Altered Mitochondrial Translation in Parkinson’s Disease." Cells 9, no. 12 (December 2, 2020): 2580. http://dx.doi.org/10.3390/cells9122580.

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Abstract:

The pathological hallmark of Parkinson’s disease (PD) is the loss of neuromelanin-containing dopaminergic neurons within the substantia nigra pars compacta (SNpc). Additionally, numerous studies indicate an altered synaptic function during disease progression. To gain new insights into the molecular processes underlying the alteration of synaptic function in PD, a proteomic study was performed. Therefore, synaptosomes were isolated by density gradient centrifugation from SNpc tissue of individuals at advanced PD stages (N = 5) as well as control subjects free of pathology (N = 5) followed by mass spectrometry-based analysis. In total, 362 proteins were identified and assigned to the synaptosomal core proteome. This core proteome comprised all proteins expressed within the synapses without regard to data analysis software, gender, age, or disease. The differential analysis between control subjects and PD cases revealed that CD9 antigen was overrepresented and fourteen proteins, among them Thymidine kinase 2 (TK2), mitochondrial, 39S ribosomal protein L37, neurolysin, and Methionine-tRNA ligase (MARS2) were underrepresented in PD suggesting an alteration in mitochondrial translation within synaptosomes.

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Journal articles on the topic 'Synaptic proteins loss'

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