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Altered synaptic function is thought to play a role in many neurodegenerative diseases, but little is known about the underlying mechanisms for synaptic dysfunction. The squid giant synapse (SGS) is a classical model for studying synaptic electrophysiology and ultrastructure, as well as molecular mechanisms of neurotransmission. Here, we conduct a multidisciplinary study of synaptic actions of misfolded human G85R-SOD1 causing familial amyotrophic lateral sclerosis (ALS). G85R-SOD1, but not WT-SOD1, inhibited synaptic transmission, altered presynaptic ultrastructure, and reduced both the size of the readily releasable pool (RRP) of synaptic vesicles and mobility from the reserved pool (RP) to the RRP. Unexpectedly, intermittent high-frequency stimulation (iHFS) blocked inhibitory effects of G85R-SOD1 on synaptic transmission, suggesting aberrant Ca2+ signaling may underlie G85R-SOD1 toxicity. Ratiometric Ca2+ imaging showed significantly increased presynaptic Ca2+ induced by G85R-SOD1 that preceded synaptic dysfunction. Chelating Ca2+ using EGTA prevented synaptic inhibition by G85R-SOD1, confirming the role of aberrant Ca2+ in mediating G85R-SOD1 toxicity. These results extended earlier findings in mammalian motor neurons and advanced our understanding by providing possible molecular mechanisms and therapeutic targets for synaptic dysfunctions in ALS as well as a unique model for further studies.
Pubmed ID: 32188708
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Private non-profit laboratory at the University of Chicago that works on scientific discovery of biodiversity, understanding the environment and exploring the human condition through education and research.
View all literature mentionsTHIS RESOURCE IS NO LONGER IN SERVICE. Documented on May 5,2022.Tool that predicts interactions between transcription factors and their regulated genes from binding motifs. Understanding vertebrate development requires unraveling the cis-regulatory architecture of gene regulation. PRISM provides accurate genome-wide computational predictions of transcription factor binding sites for the human and mouse genomes, and integrates the predictions with GREAT to provide functional biological context. Together, accurate computational binding site prediction and GREAT produce for each transcription factor: 1. putative binding sites, 2. putative target genes, 3. putative biological roles of the transcription factor, and 4. putative cis-regulatory elements through which the factor regulates each target in each functional role.
View all literature mentionsTHIS RESOURCE IS NO LONGER IN SERVICE, documented on July 17, 2013. The center serves the biomedical research community's increased needs for alternative invertebrate models by maintaining a consistent year-round supply of live cephalopod mollusks. These animals are suitable for a wide range of physiological and molecular biological investigations. Investigations are being conducted in the area of life history related to improved animal husbandry. Further studies focus on improving culture system design through development of computer automation and innovative water filtration technology. Current biomedical research on cephalopods includes neurophysiology of the giant axon; anatomy and neurophysiology of the equilibrium receptor organ as a comparative model of the vestibular system of invertebrates; chemoreception, basic nutrition, and protein metabolism; cellular receptor function; and brain, behavior, and learning. Services Provided: The center has built a computer-automated, environmentally controlled, recirculating seawater laboratory for the purpose of culturing cephalopods. The tank systems can be used to conduct a variety of experiments never before possible with cephalopods. Visiting researchers have access to dedicated facilities, including wet and dry laboratory space, office space, computer support and accommodations, as well as priority access to all available live animal resources. Off-site investigators can have live animals, dissected animal tissues/body fluids from all life stages, and a variety of molecular reagents (gene libraries and clones) delivered year-round. Staff expertise and an extensive literature library are available. All life stages of the squid (Sepioteuthis lessoniana) and the common cuttlefish (Sepia officinalis) are available year-round from laboratory culture populations. The sepiolid squid (Euprymna scolopes) can also be cultured on request. The squid Lolliguncula brevis is available year-round from local waters; the squids Loligo opalescens, L. pealeii, and L. plei can be obtained seasonally on request. The chambered nautilus, Nautilus pompilius, and Octopus bimaculoides are available on request. Animal costs vary by species and size. Any tissue or body fluid from these animals can also be provided. Fees for special services are negotiated on a case-by-case basis.
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