Williams Syndrome
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Transcript of Williams Syndrome
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Williams Syndrome
Natalie DeCheck
Image from: http://mindbodyshift.wordpress.com/2010/05/18/an-unquenchable-thirst-for-love-the-paradox-of-living-with-williams-syndrome/
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What is Williams Syndrome?
Physical characteristics:•“elfin” facial features•narrowing of aorta or pulmonary arteries•musculoskeletal problems•sensitive hearing•short stature and slow weight gain
Behavioral characteristics:
•exceptional music and linguistic abilities•poor numerical abilities•lack of visuospatial abilities •lack of social inhibition•mental retardation•general anxiety
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What is Williams Syndrome?
Image from : Bellugi, U.,Wang, P. P., & Jernigan, T. L. (1994).Williams syndrome: An unusual neuropsychological profile. In S. H. Broman & J. Grafman (Eds.), A typical cognitive deficits in developmentaldisorders: Implications for brain function (pp. 23–56). Hillsdale, NJ: Lawrence Erlbaum.
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What causes Williams Syndrome?
Image from: Francke U. Williams-Beuren syndrome: genes and mechanisms. Hum Mol Genet. 1999;8:1947–1954.
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LIMK1 affects visuospatial cognition
http://neuralmodel.net/library/brain/parietal_cortex.htm
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... But how?
Biological ProcessesRho protein signal transduction, actin cytoskeleton organization, axon guidance, negative regulation of ubiquitin protein ligase activity, positive regulation of actin filament bundle assembly, positive regulation of axon extension
Cellular componentcytosol, neuron projection, nucleus
Molecular FunctionATP binding, heat shock protein binding, protein serine/threonine
kinase activity, zinc ion binding
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How does the actin cytoskeleton affect nervous
system development?neuron pathfinding!
http://www3.utsouthwestern.edu/psychlab/cowan/
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LIMK1 regulates actin cytoskeleton organization in
hippocampus
WT KO LIMK1 Meng, Y., Zhang, Y., Tregoubov, V., Janus, C., Cruz, L., Jackson, M., Lu, W.Y., MacDonald, J.F., Wang, J.Y., Falls, D.L., and Jia, Z. (2002). Neuron 35, this issue, 121–133.
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How does LIMK1 interact with other
proteins?
Image from: String Interaction Network 9.0
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Proteins expressed in human brain tissue
Image from: String Interaction Network 9.0
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LIMK1 - binding domains
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Binding domains of interacting proteins
SSH1
CLF1
PAK1
Rac1
PAK4
Images from PFAM
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Main hypothesis: Deletion of LIMK1 alters actin cytoskeleton organization of parietal neurons.
Experiment 1: Establish where
LIMK1 and interacting proteins localize in parietal
neurons
Experiment 2: Establish the role of
cofilin in actin cytoskeleton
organization in parietal neurons
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Model Organism
http://adasperdown.blogspot.com/2012/02/mouse-remorse.html
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Generated using TCoffee
Homologs of LIMK1
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Protein interaction in humans
Image from: String Interaction Network 9.0
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Protein interactions in mus musculus
Image from: String Interaction Network 9.0
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Experiment 1Question: How does LIMK1 and its interacting proteins localize in parietal neurons?
Method:
Immunofluorescence - GFP (determine localization)
2. In LIMK1 WT and KO mice:
1. RNAi to knockout LIMK1 (WS phenotype)
Microarray (determine expression)
http://anthropology.net/2008/02/29/differences-of-gene-expression-between-human-populations/microarray/
http://www.wadsworth.org/cores/alm/gallery.htm
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Cofilin - LIMK1 interaction
http://www.ncbi.nlm.nih.gov/pubmed/16230460
Activates
Inactivates1. 2.XLIMK1
CFL1
inhibition of neurite transport and synaptic loss in many cognitive disorders
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Previous studies have shown decreased spine area and length of postsynaptic density in hippocampus when LIMK1 is deleted (via effect on actin filament
dynamics through hyperactivation of cofilin)
Samiere PD, Bamburg JR. Head, neck, and spines: a role for LIMK-1 in the hippocampus. Neuron. 2002;35:3-5/
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Experiment 2 Question: What is the role of cofilin in actin cytoskeleton organization in parietal neurons?Method:
1. RNAi (generate KO LIMK1 mice)
Microarray (determine expression)
Immunohistochemistry- (determine
phosphorylation (inactivation) of cofilin)
Immunofluorescence - GFP (determine localization)
2. In LIMK1 WT and KO:
http://www.sciencedirect.com/science/article/pii/S0169328X0200445X
http://www.jbc.org/content/282/32/23491/F5.expansion.html
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Future research
Can LIMK1 be linked to anxiety in WS patients?
Chemical screen - regulate cofilin activation
http://www.kcl.ac.uk/depsta/biomedical/randall/methods/im-fluo.html
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SourcesGungabissoon, R.A., and Bamburg, J.R. (2003). Regulation of growth cone actin dynamics by ADF/Cofilin. J. Histochem. Cytochem. 51, 411–420.
Meng Y, Takahashi H, Meng J, Zhang Y, Lu G, Asrar S, Nakamura T, Jia Z. Regulation of ADF/cofilin phosphorylation and synaptic function by LIM-kinase. Neuropharmacology. 2004;47:746–754.
Samiere PD, Bamburg JR. Head, neck, and spines: a role for LIMK-1 in the hippocampus. Neuron. 2002;35:3-5/
Meng Y, Zhang Y, Tregoubov V, Janus C, Cruz L, Jackson M, Lu WY, MacDonald JF, Wang JY, Falls DL, and Jia Z. Abnormal spine morphology and enhanced LTP in LIMK-1 knockout mice. Neuron 35: 121–133, 2002.
http://www.braincenteramerica.com/visuospa.php
http://www.pdb.org/pdb/explore/explore.do?structureId=3S95
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Questions?
http://www.wadsworth.org/cores/alm/gallery.htm