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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. RSK2. MAPs.

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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 RSK2 MAPs Mnk1/2 P eIF4E CBP CREB CRE Protein Synthesis Spine Structure Nucleus Gene Expression

  3. 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 Neurofibromatosis MR RSK2 MAPs Mnk1/2 P eIF4E CBP CREB CRE Protein Synthesis Spine Structure Nucleus Gene Expression

  4. + + 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.

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

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

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

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

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

  10. 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

  11. 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

  12. 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.

  13. Angelman Syndrome- Clinical Features • Severe MR • Absent speech • Happy disposition • Seizures

  14. Ube3a codes for an E6-AP Ubiquitin Ligase • Ube3a Ubiquitin Ligase • Maternal Imprinting of Ube3a • Expression of E6-AP in the Hippocampus and Cerebellum

  15. Ube3a Deletion, Mutation Uniparental Disomy Mismethylation

  16. 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.

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

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

  19. AS mouse model LTP

  20. Saturating HFS-induced LTP

  21. NMDAR Independent LTP

  22. Pathogenesis of Angelman Syndrome E6-AP ? P53 HHR23A E6-AP MCM7

  23. PKA MEK Adenylyl Cyclase PLC Ca++ Channel NMDA Receptor ATP Ca++ CaM cAMP DAG PKC CaMKII Ras B-Raf Rap1 Raf-1 Ras ERK

  24. Total Kinase Concentrations are Normal A

  25. Increased P-Thr286 CaMKII in AS Mice a Total CaMKII 286 a P-Thr CaMKII * 180 WT m-/p+ WT m-/p+ 160 140 120 100 Immunoreactivity (% of Control) 80 60 40 20 0 P-PKA P-PKC P-CaMKII P-ERK p42 A

  26. Reduced Post-Hoc CaMKII Phosphorylation

  27. CAM Ca2+ Thr 286 Regulatory Subunit aCaMKII Catalytic Subunit

  28. CAM Ca2+ P aCaMKII Catalytic Subunit Autonomously Active Thr 286 Regulatory Subunit

  29. Hippocampal CaMKII Activity

  30. CAM Ca2+ Thr 286 Thr 305 Regulatory Subunit aCaMKII Catalytic Subunit

  31. CAM Ca2+ P P aCaMKII Catalytic Subunit Inactive Thr 305 Thr 286 Regulatory Subunit

  32. Purified CaMKII Hippocampal Homogenates 2+ 2+ 2+ +Ca /CaM +Ca /CaM +Ca /CaM Ctrl Ctrl Ctrl b CaMKII a CaMKII Control Peptide Block 305/306 a Thr CaMKII Total CaMKII WT m-/p+ WT m-/p+ b CaMKII a CaMKII 150 * 125 100 Immunoreactivity (% of Control) 75 50 25 0 Wildtype m-/p+

  33. Purified CaMKII Hippocampal Homogenates 2+ 2+ 2+ +Ca /CaM +Ca /CaM +Ca /CaM Ctrl Ctrl Ctrl b CaMKII a CaMKII Control Peptide Block 305/306 a Thr CaMKII Total CaMKII WT m-/p+ WT m-/p+ b CaMKII a CaMKII 150 * 125 100 Immunoreactivity (% of Control) 75 50 25 0 Wildtype m-/p+

  34. aCaMKII T305D Mice are Impaired in LTP 220 200 180 160 Wild type 140 120 No aCaMKII Inhibited 100 WT T305D 100 Hz/1s 80 CaMKII a 60 -10 0 10 20 30 40 50 60 Time (min) Elgersma et al.

  35. T305D Mutants Have Impaired Fear-Conditioned Learning Elgersma et al.

  36. CAM Ca2+ P P aCam KII Catalytic Subunit Inactive Thr 305 Thr 286 Regulatory Subunit

  37. NR1 NR2B P P CaMKII PP1 ? E6-AP PP2A CaMKII

  38. AS Mouse Model-Conclusions • Aberrant hyper-autophosphorylation of CaMKII in Angelman mouse hippocampus. • Altered phosphatase activity (PP1 and/or PP2A). • Alterations in CaMKII autophosphorylation can explain the physiologic and behavioral deficits in our model. • A role for CaMKII activity in human learning.

  39. 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

  40. 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

  41. Mental Retardation Syndromes Disruptions of memory-related signal transduction systems. Impact of basic research on clinically relevant studies, and vice-versa. Identifying new avenues of treatment.

  42. 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

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