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Inherited Disorders of Human Memory: Mental Retardation Syndromes

Inherited Disorders of Human Memory: Mental Retardation Syndromes. From Mechanisms of Memory by J. David Sweatt, Ph.D. Ras. R 2. R 4. Grb. R 3. R 1. SOS. PKC. AC. GEF. G Protein. PKA. Ca 2+. Ca 2+. NO. Raf1. NF1. Rap. B-Raf. NF1 GAP. MEK1/2. ERK1/2.

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Inherited Disorders of Human Memory: Mental Retardation Syndromes

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  1. Inherited Disorders of Human Memory:Mental Retardation Syndromes From Mechanisms of Memory by J. David Sweatt, Ph.D.

  2. Ras R2 R4 Grb R3 R1 SOS PKC AC GEF G Protein PKA Ca2+ Ca2+ NO. Raf1 NF1 Rap B-Raf NF1 GAP MEK1/2 ERK1/2 Coffin-Lowry Syndrome Neurofibromatosis MR RSK2 Rubinstein-Taybi Syndrome MAPs Mnk1/2 P eIF4E CBP CREB CRE Protein Synthesis Spine Structure Nucleus Gene Expression Fragile X Syndrome

  3. + + Activation of ras Inactive Active PO4 ras ras GTP Hydrolysis GDP GTP GAPs GTPase Activating Proteins e.g. NF1, SynGAP GTP GEFs Guanine Nucleotide Exchange Factor Proteins e.g. SOS, cAMP GEF, Ca2+/DAG GEF, ras GRF Weeber and Sweatt. Neuron 33:845-848.

  4. Ras-dependent Spatial Learning in Nf1+/- Animals K-ras N-ras Farnesyl Transferase Inhibitor Costa et al (2002) Nature 415:526-530.

  5. Ras-dependent LTP deficits in Nf1+/- animals Costa et al (2002) Nature 415:526-530.

  6. E1 Charging The Ubiquitination Pathway Ub E1 Ub Step 1 E1 E1 ATP Step 2 E2 Charging Ub E2—E3 Transfer E2 Ub Step 4 Ligase Complex Formation Step 3 E2 E3 Ub Ligase Target E3 Protein Target Poly-Ubiquitination Target Step 5 Ub Ub Ub Protein Ub Ub Weeber and Sweatt (2000) Recent Res. Devel. Neurochem. 3:289-299.

  7. Selective Deficit in Context-dependent Fear conditioning in Ube3a Maternal Deficient Mice Jiang et al (1998) Neuron 21:799-811.

  8. Impairment of hippocampal LTP in Ube3a Maternal Deficient mice Jiang et al (1998) Neuron 21:799-811.

  9. Current Model of Fragile X Mental Retardation Coding Region Regulatory Region Gene Structure FMR1 Gene CGG Expansion in Regulatory Region Point Mutation in Coding Region Disruption Of FMR1 Gene Loss of FMR1 Protein (FMRP) FMRP = 63K RNA binding protein that binds to poly (G) and poly (U) structures FMRP Structure KH Domain KH Domain FMR1/FXR Interaction domain Ribosome Interaction Domain RGG Box RGG Box = Arginine & Glycine-rich domain KH domain = Ribonucleoprotein K homology domain

  10. A B 250 250 200 200 (Standardized to Baseline) (Standardized to Baseline) Slope fEPSP Slope fEPSP 150 150 100 100 Wildtype Wildtype Mutant Mutant 50 50 -20 -10 0 10 20 30 40 50 60 -20 -10 0 10 20 30 40 50 60 C D Time (min) Time (min) 300 200 200 150 (Standardized to Baseline) (Standardized to Baseline) Slope fEPSP Slope fEPSP 100 100 Wildtype Wildtype Mutant Mutant 0 50 -20 -10 0 10 20 30 40 50 60 70 80 -30 -20 -10 0 10 20 30 40 50 60 Time (min) Time (min) Enhanced LTP in FMR2 knockout mice Gu et al. (2002) J. Neurosci. 22:2753-2763.

  11. Williams Syndrome rho PKC rac PAK, ROCK LIMK-1 (Williams Syndrome) Direct phosphorylation (inhibitory) Actin Depolymerization Factor (ADF) / cofilin ADF / Cofilin promotes Actin depolymerization Actin Cytoskeleton—Loss of LIMK-1 causes increased actin turnover Altered Dendritic Spine Augmented LTP, Learning Impairments

  12. Nonsyndromic X-Linked Mental Retardation Dbl (Diffuse B-cell Lymphoma) Rho GEF6 Rho GAP Rho GDI GEFs + _ Rho PAK3 (p21 Activated Kinase) JNK p38 LTD disruption? raf-1 Cytoskeleton

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