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https://www.readbyqxmd.com/read/28422131/variants-in-cplx1-in-two-families-with-autosomal-recessive-severe-infantile-myoclonic-epilepsy-and-id
#1
Silke Redler, Tim M Strom, Thomas Wieland, Kirsten Cremer, Hartmut Engels, Felix Distelmaier, Jörg Schaper, Alma Küchler, Johannes R Lemke, Stephanie Jeschke, Nicole Schreyer, Heinrich Sticht, Margarete Koch, Hermann-Josef Lüdecke, Dagmar Wieczorek
For a large number of individuals with intellectual disability (ID), the molecular basis of the disorder is still unknown. However, whole-exome sequencing (WES) is providing more and more insights into the genetic landscape of ID. In the present study, we performed trio-based WES in 311 patients with unsolved ID and additional clinical features, and identified homozygous CPLX1 variants in three patients with ID from two unrelated families. All displayed marked developmental delay and migrating myoclonic epilepsy, and one showed a cerebellar cleft in addition...
April 19, 2017: European Journal of Human Genetics: EJHG
https://www.readbyqxmd.com/read/28392696/compound-porcine-cerebroside-and-ganglioside-injection-attenuates-cerebral-ischemia-reperfusion-injury-in-rats-by-targeting-multiple-cellular-processes
#2
Mingyang Wang, Yi Zhang, Lu Feng, Ji Zheng, Shujie Fan, Junya Liu, Nan Yang, Yanyong Liu, Pingping Zuo
BACKGROUND: Compound porcine cerebroside and ganglioside injection (CPCGI) is a neurotrophic drug used clinically to treat certain functional disorders of brain. Despite its extensive usage throughout China, the exact mechanistic targets of CPCGI are unknown. This study was carried out to investigate the protective effect of CPCGI against ischemic neuronal damage in rats with middle cerebral artery occlusion (MCAO) reperfusion injury and to investigate the neuroprotective mechanisms of CPCGI...
2017: Neuropsychiatric Disease and Treatment
https://www.readbyqxmd.com/read/28330839/evolutionary-insights-into-t-type-ca-2-channel-structure-function-and-ion-selectivity-from-the-trichoplax-adhaerens-homologue
#3
Carolyn L Smith, Salsabil Abdallah, Yuen Yan Wong, Phuong Le, Alicia N Harracksingh, Liana Artinian, Arianna N Tamvacakis, Vincent Rehder, Thomas S Reese, Adriano Senatore
Four-domain voltage-gated Ca(2+) (Cav) channels play fundamental roles in the nervous system, but little is known about when or how their unique properties and cellular roles evolved. Of the three types of metazoan Cav channels, Cav1 (L-type), Cav2 (P/Q-, N- and R-type) and Cav3 (T-type), Cav3 channels are optimized for regulating cellular excitability because of their fast kinetics and low activation voltages. These same properties permit Cav3 channels to drive low-threshold exocytosis in select neurons and neurosecretory cells...
April 3, 2017: Journal of General Physiology
https://www.readbyqxmd.com/read/28239029/comprehensive-analysis-of-gene-mutation-and-expression-profiles-in-neuroendocrine-carcinomas-of-the-stomach
#4
Rie Makuuchi, Masanori Terashima, Masatoshi Kusuhara, Takashi Nakajima, Masakuni Serizawa, Keiichi Hatakeyama, Keiichi Ohshima, Kenichi Urakami, Ken Yamaguchi
The gene mutation and expression profiles of gastric neuroendocrine carcinoma (NEC) have not been comprehensively determined. Here, we examined the gene mutation and expression profiles of NEC using whole exome sequencing (WES) and microarray analysis. Six patients with gastric NEC and 13 with gastric adenocarcinoma (GAD) were included in this study. Single nucleotide variants were compared and multivariate statistical investigation with orthogonal partial least squares discriminant analysis (OPLS-DA) was performed to compare the difference in expression profiles between NEC and GAD...
2017: Biomedical Research
https://www.readbyqxmd.com/read/28111077/synaptotagmin-1-and-synaptotagmin-7-dependent-fusion-mechanisms-target-synaptic-vesicles-to-kinetically-distinct-endocytic-pathways
#5
Ying C Li, Natali L Chanaday, Wei Xu, Ege T Kavalali
Synaptic vesicle recycling is essential for maintaining normal synaptic function. The coupling of exocytosis and endocytosis is assumed to be Ca(2+) dependent, but the exact role of Ca(2+) and its key effector synaptotagmin-1 (syt1) in regulation of endocytosis is poorly understood. Here, we probed the role of syt1 in single- as well as multi-vesicle endocytic events using high-resolution optical recordings. Our experiments showed that the slowed endocytosis phenotype previously reported after syt1 loss of function can also be triggered by other manipulations that promote asynchronous release such as Sr(2+) substitution and complexin loss of function...
February 8, 2017: Neuron
https://www.readbyqxmd.com/read/28108469/blood-rna-biomarkers-in-prodromal-park4-and-rem-sleep-behavior-disorder-show-role-of-complexin-1-loss-for-risk-of-parkinson-s-disease
#6
Suna Lahut, Suzana Gispert, Özgür Ömür, Candan Depboylu, Kay Seidel, Jorge Antolio Domínguez-Bautista, Nadine Brehm, Hülya Tireli, Karl Hackmann, Caroline Pirkevi, Barbara Leube, Vincent Ries, Kerstin Reim, Nils Brose, Wilfred F den Dunnen, Madrid Johnson, Zsuzsanna Wolf, Marc Schindewolf, Wiebke Schrempf, Kathrin Reetz, Peter Young, David Vadasz, Achilleas S Frangakis, Evelin Schröck, Helmuth Steinmetz, Marina Jendrach, Udo Rüb, Ayşe Nazlı Başak, Wolfgang Oertel, Georg Auburger
Parkinson's disease (PD) is a frequent neurodegenerative process at old age. Accumulation and aggregation of the lipid-binding SNARE complex component alpha-synuclein (SNCA) underlies this vulnerability and defines stages of disease progression. Determinants of SNCA levels and mechanisms of SNCA neurotoxicity are intensely investigated. In view of physiological SNCA roles in blood to modulate vesicle release, we studied blood samples from a new large pedigree with SNCA gene duplication (PARK4 mutation), to identify effects of SNCA gain-of-function as potential disease biomarkers...
January 20, 2017: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/28077717/complexin-mutants-reveal-partial-segregation-between-recycling-pathways-that-drive-evoked-and-spontaneous-neurotransmission
#7
Nadezhda Sabeva, Richard W Cho, Alexander Vasin, Agustin Gonzalez, J Troy Littleton, Maria Bykhovskaia
Synaptic vesicles fuse at morphological specializations in the presynaptic terminal termed active zones (AZs). Vesicle fusion can occur spontaneously or in response to an action potential. Following fusion, vesicles are retrieved and recycled within nerve terminals. It is still unclear whether vesicles that fuse spontaneously or following evoked release share similar recycling mechanisms. Genetic deletion of the SNARE-binding protein complexin dramatically increases spontaneous fusion, with the protein serving as the synaptic vesicle fusion clamp at Drosophila synapses...
January 11, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/27913592/complexin-mutants-reveal-partial-segregation-between-recycling-pathways-that-drive-evoked-and-spontaneous-neurotransmission
#8
Nadezhda Sabeva, Richard W Cho, Alexander Vasin, Agustin Gonzalez, J Troy Littleton, Maria Bykhovskaia
Synaptic vesicles fuse at morphological specializations in the presynaptic terminal termed active zones (AZs). Vesicle fusion can occur spontaneously or in response to an action potential. Following fusion, vesicles are retrieved and recycled within nerve terminals. It is still unclear whether vesicles that fuse spontaneously or following evoked release share similar recycling mechanisms. Genetic deletion of the SNARE-binding protein complexin dramatically increases spontaneous fusion, with the protein serving as the synaptic vesicle fusion clamp at Drosophila synapses...
December 2, 2016: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/27881774/interactions-between-snap-25-and-synaptotagmin-1-are-involved-in-vesicle-priming-clamping-spontaneous-and-stimulating-evoked-neurotransmission
#9
Melanie Schupp, Jörg Malsam, Marvin Ruiter, Andrea Scheutzow, Keimpe D B Wierda, Thomas H Söllner, Jakob B Sørensen
Whether interactions between synaptotagmin-1 (syt-1) and the soluble NSF attachment protein receptors (SNAREs) are required during neurotransmission is debated. We examined five SNAP-25 mutations designed to interfere with syt-1 interactions. One mutation, D51/E52/E55A, targeted negative charges within region II of the primary interface (Zhou et al., 2015); two mutations targeted region I (D166A and D166/E170A) and one mutation targeted both (D51/E52/E55/D166A). The final mutation (D186/D193A) targeted C-terminal residues not expected to interact with syt-1...
November 23, 2016: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/27866231/presynaptic-proteins-complexin-i-and-complexin-ii-differentially-influence-cognitive-function-in-early-and-late-stages-of-alzheimer-s-disease
#10
Alfredo Ramos-Miguel, Ken Sawada, Andrea A Jones, Allen E Thornton, Alasdair M Barr, Sue E Leurgans, Julie A Schneider, David A Bennett, William G Honer
Progressive accumulation of Alzheimer's disease-related pathology is associated with cognitive dysfunction. Differences in cognitive reserve may contribute to individual differences in cognitive function in the presence of comparable neuropathology. The protective effects of cognitive reserve could contribute differentially in early versus late stages of the disease. We investigated presynaptic proteins as measures of brain reserve (a subset of total cognitive reserve), and used Braak staging to estimate the progression of Alzheimer's disease...
March 2017: Acta Neuropathologica
https://www.readbyqxmd.com/read/27821736/c-terminal-domain-of-mammalian-complexin-1-localizes-to-highly-curved-membranes
#11
Jihong Gong, Ying Lai, Xiaohong Li, Mengxian Wang, Jeremy Leitz, Yachong Hu, Yunxiang Zhang, Ucheor B Choi, Daniel Cipriano, Richard A Pfuetzner, Thomas C Südhof, Xiaofei Yang, Axel T Brunger, Jiajie Diao
In presynaptic nerve terminals, complexin regulates spontaneous "mini" neurotransmitter release and activates Ca(2+)-triggered synchronized neurotransmitter release. We studied the role of the C-terminal domain of mammalian complexin in these processes using single-particle optical imaging and electrophysiology. The C-terminal domain is important for regulating spontaneous release in neuronal cultures and suppressing Ca(2+)-independent fusion in vitro, but it is not essential for evoked release in neuronal cultures and in vitro...
November 22, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27806277/interaction-of-the-complexin-accessory-helix-with-synaptobrevin-regulates-spontaneous-fusion
#12
Alexander Vasin, Dina Volfson, J Troy Littleton, Maria Bykhovskaia
Neuronal transmitters are released from nerve terminals via the fusion of synaptic vesicles with the plasma membrane. Vesicles attach to membranes via a specialized protein machinery composed of membrane-attached (t-SNARE) and vesicle-attached (v-SNARE) proteins that zipper together to form a coiled-coil SNARE bundle that brings the two fusing membranes into close proximity. Neurotransmitter release may occur either in response to an action potential or through spontaneous fusion. A cytosolic protein, Complexin (Cpx), binds the SNARE complex and restricts spontaneous exocytosis by acting as a fusion clamp...
November 1, 2016: Biophysical Journal
https://www.readbyqxmd.com/read/27525480/insulin-signaling-controls-neurotransmission-via-the-4ebp-dependent-modification-of-the-exocytotic-machinery
#13
Rebekah Elizabeth Mahoney, Jorge Azpurua, Benjamin A Eaton
Altered insulin signaling has been linked to widespread nervous system dysfunction including cognitive dysfunction, neuropathy and susceptibility to neurodegenerative disease. However, knowledge of the cellular mechanisms underlying the effects of insulin on neuronal function is incomplete. Here, we show that cell autonomous insulin signaling within the Drosophila CM9 motor neuron regulates the release of neurotransmitter via alteration of the synaptic vesicle fusion machinery. This effect of insulin utilizes the FOXO-dependent regulation of the thor gene, which encodes the Drosophila homologue of the eif-4e binding protein (4eBP)...
August 15, 2016: ELife
https://www.readbyqxmd.com/read/27444020/n-terminal-domain-of-complexin-independently-activates-calcium-triggered-fusion
#14
Ying Lai, Ucheor B Choi, Yunxiang Zhang, Minglei Zhao, Richard A Pfuetzner, Austin L Wang, Jiajie Diao, Axel T Brunger
Complexin activates Ca(2+)-triggered neurotransmitter release and regulates spontaneous release in the presynaptic terminal by cooperating with the neuronal soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs) and the Ca(2+)-sensor synaptotagmin. The N-terminal domain of complexin is important for activation, but its molecular mechanism is still poorly understood. Here, we observed that a split pair of N-terminal and central domain fragments of complexin is sufficient to activate Ca(2+)-triggered release using a reconstituted single-vesicle fusion assay, suggesting that the N-terminal domain acts as an independent module within the synaptic fusion machinery...
August 9, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27417722/gene-expression-of-proteins-of-the-vesicle-cycle-in-dopaminergic-neurons-in-modeling-of-parkinson-s-disease
#15
E R Mingazov, M V Ugrumov
It is assumed that one of the causes of the degeneration of dopaminergic neurons is the dysregulation of the vesicle cycle, which is ensured by a number of proteins including syntaxin I, synaptotagmin I, complexins I and II, and Rab5. It was shown that there is a compensatory increase in gene expression of proteins responsible for exocytosis at the preclinical stage of Parkinson's disease (PD) in the in substantia nigra (SN) in mice. Conversely, in the model of the clinical stage of PD, the decreases of gene expression of proteins responsible for exocytosis, endocytosis, and neuronal survival, which may be among the triggers of motor dysfunctions...
May 2016: Doklady. Biochemistry and Biophysics
https://www.readbyqxmd.com/read/27335398/functional-roles-of-complexin3-and-complexin4-at-mouse-photoreceptor-ribbon-synapses
#16
Norbert Babai, Anna Sendelbeck, Hanna Regus-Leidig, Michaela Fuchs, Jasmin Mertins, Kerstin Reim, Nils Brose, Andreas Feigenspan, Johann Helmut Brandstätter
UNLABELLED: Complexins (Cplxs) are SNARE complex regulators controlling the speed and Ca(2+) sensitivity of SNARE-mediated synaptic vesicle fusion. We have shown previously that photoreceptor ribbon synapses in mouse retina are equipped with Cplx3 and Cplx4 and that lack of both Cplxs perturbs photoreceptor ribbon synaptic function; however, Cplx3/4 function in photoreceptor synaptic transmission remained elusive. To investigate Cplx3/4 function in photoreceptor ribbon synapses, voltage-clamp recordings from postsynaptic horizontal cells were performed in horizontal slice preparations of Cplx3/4 wild-type (WT) and Cplx3/4 double knock-out (DKO) mice...
June 22, 2016: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/27335030/identification-of-novel-key-molecules-involved-in-spatial-memory-impairment-in-triple-transgenic-mice-of-alzheimer-s-disease
#17
Ming Ying, Xiaojing Sui, Yanling Zhang, Qian Sun, Zhongsen Qu, Xiaobin Luo, Raymond Chuen-Chung Chang, Jiazuan Ni, Jianjun Liu, Xifei Yang
The molecular mechanisms underlying cognitive impairment in Alzheimer's disease (AD) remain largely unclear. In the present study, we were aimed to identify the potential key molecules involved in spatial memory impairment in a triple transgenic (3xTg-AD) mouse model of AD. By employing two-dimensional fluorescence difference gel electrophoresis (2D-DIGE) coupled with mass spectrometry, we revealed a total of 24 differentially expressed proteins in hippocampus of 9-month-old 3xTg-AD mice with significant spatial memory impairment in comparison to the age-matched controls...
June 22, 2016: Molecular Neurobiology
https://www.readbyqxmd.com/read/27286417/preincubation-of-t-snares-with-complexin-i-increases-content-mixing-efficiency
#18
Jaewook Kim, Yicheng Zhu, Yeon-Kyun Shin
Complexin (Cpx) is a major regulator for Ca(2+)-triggered fast neuroexocytosis which underlies neuronal communication. Many psychiatric and neurological disorders accompany changes in the Cpx expression level, suggesting that abnormal Cpx levels may elicit aberrant cognitive symptoms. To comprehend how the changes in the Cpx level might affect neuronal communication, we investigated Ca(2+)-triggered exocytosis at various Cpx concentrations. Ca(2+)-triggered content-mixing between a single proteoliposome of t-SNARE and another single proteoliposome of v-SNARE plus Ca(2+)-sensor synaptotagmin 1 was examined with total internal reflection microscopy...
July 5, 2016: Biochemistry
https://www.readbyqxmd.com/read/27239031/complexin-3-increases-the-fidelity-of-signaling-in-a-retinal-circuit-by-regulating-exocytosis-at-ribbon-synapses
#19
Lena S Mortensen, Silvia J H Park, Jiang-Bin Ke, Benjamin H Cooper, Lei Zhang, Cordelia Imig, Siegrid Löwel, Kerstin Reim, Nils Brose, Jonathan B Demb, Jeong-Seop Rhee, Joshua H Singer
Complexin (Cplx) proteins modulate the core SNARE complex to regulate exocytosis. To understand the contributions of Cplx to signaling in a well-characterized neural circuit, we investigated how Cplx3, a retina-specific paralog, shapes transmission at rod bipolar (RB)→AII amacrine cell synapses in the mouse retina. Knockout of Cplx3 strongly attenuated fast, phasic Ca(2+)-dependent transmission, dependent on local [Ca(2+)] nanodomains, but enhanced slower Ca(2+)-dependent transmission, dependent on global intraterminal [Ca(2+)] ([Ca(2+)]I)...
June 7, 2016: Cell Reports
https://www.readbyqxmd.com/read/27222590/complexin-splits-the-membrane-proximal-region-of-a-single-snarepin
#20
Linxiang Yin, Jaewook Kim, Yeon-Kyun Shin
Complexin (Cpx) is thought to be a major regulator of soluble N-ethylmaleimide-sensitive factor-attachment protein receptor (SNARE)-dependent membrane fusion. Although the inhibition of membrane fusion by Cpx has been frequently reported, its structural basis has been elusive and an anticipated disruption of the SNARE core has never been observed. In the present study, to mimic the natural environment, we assembled a single SNAREpin between two nanodisc membrane patches. Single-molecule FRET (smFRET) detects a large conformational change, specifically at the C-terminal half, whereas no conformational change is observed at the N-terminal half...
July 15, 2016: Biochemical Journal
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