Upload
jon
View
28
Download
1
Tags:
Embed Size (px)
DESCRIPTION
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. - PowerPoint PPT Presentation
Citation preview
Inherited Disorders of Human Memory:
Mental Retardation Syndromes
From Mechanisms of Memory by J. David Sweatt, Ph.D.
ERK1/2
MEK1/2
Raf1
R1Grb
SOSRas
PKC
R2
B-Raf
PKA
R3
Rap
AC
Gene Expression
Mnk1/2
eIF4E
Protein Synthesis
MAPs
Spine Structure
CRE
CREB
P
CBP
RSK2
GEF
NF1GAP
Neurofibromatosis MR
NO.
Ca2+
G Protein
NF1
Ca2+
Nucleus
R4
Coffin-Lowry Syndrome
Rubinstein-TaybiSyndrome
Fragile X Syndrome
PO4
ras rasGDP GTP
GTP
GTP Hydrolysis
GAPsGTPase Activating Proteins
e.g. NF1, SynGAP
GEFsGuanine Nucleotide
Exchange Factor Proteins
e.g. SOS, cAMP GEF,
Ca2+/DAG GEF, ras GRF
Inactive Active
++
Activation of ras
Weeber and Sweatt. Neuron 33:845-848.
K-ras
N-ras
Farnesyl Transferase Inhibitor
Costa et al (2002) Nature 415:526-530.
Ras-dependent Spatial Learning in Nf1+/- Animals
Ras-dependent LTP deficits in Nf1+/- animals
Costa et al (2002) Nature 415:526-530.
The Ubiquitination Pathway
Step 1
Step 2
Complex Formation
Step 3
Step 4
Step 5
E1 Charging
E2 Charging
E2—E3 Transfer
TargetPoly-
Ubiquitination
E1
E1E1
Ub Ub
ATP
E2LigaseUb
E3Ligase
TargetProtein
E2Ub
E3 TargetProtein
UbUb Ub
UbUb
Ub
Weeber and Sweatt (2000) Recent Res. Devel. Neurochem. 3:289-299.
Selective Deficit in Context-dependent Fear conditioning in Ube3a Maternal Deficient Mice
Jiang et al (1998) Neuron 21:799-811.
Impairment of hippocampal LTP in Ube3a Maternal Deficient mice
Jiang et al (1998) Neuron 21:799-811.
Current Model of Fragile X Mental RetardationCoding Region
Regulatory Region
CGG Expansion in Regulatory Region
Point Mutation in Coding Region
DisruptionOf FMR1 Gene
Loss ofFMR1 Protein (FMRP)
FMR1/FXRInteraction domain
RibosomeInteraction
Domain
RGG BoxKHDomain
KHDomain
RGG Box = Arginine & Glycine-rich domainKH domain = Ribonucleoprotein K homology domain
FMRP = 63K RNA binding protein that binds to poly (G) and poly (U) structures
FMR1 GeneGeneStructure
FMRPStructure
Enhanced LTP in FMR2 knockout mice
A
C D-20 -10 0 10 20 30 40 50 60
50
100
150
200
250
MutantWildtype
Time (min)
Slop
e fE
PSP
(Sta
ndar
dize
d to
Bas
elin
e)
Time (min)
B
-20 -10 0 10 20 30 40 50 6050
100
150
200
250
WildtypeMutant
Slop
e fE
PSP
(Sta
ndar
dize
d to
Bas
elin
e)
-20 -10 0 10 20 30 40 50 60 70 800
100
200
300
MutantWildtype
Time (min)
Slop
e fE
PSP
(Sta
ndar
dize
d to
Bas
elin
e)
-30 -20 -10 0 10 20 30 40 50 6050
100
150
200
WildtypeMutant
Time (min)
Slop
e fE
PSP
(Sta
ndar
dize
d to
Bas
elin
e)
Gu et al. (2002) J. Neurosci. 22:2753-2763.
rho
PAK, ROCK
LIMK-1(Williams Syndrome)
Actin Depolymerization Factor (ADF) / cofilin
Actin Cytoskeleton—Loss of LIMK-1causes increased actin turnover
Altered Dendritic Spine
Augmented LTP, Learning Impairments
rac PKC
Direct phosphorylation(inhibitory)
ADF / Cofilin promotesActin depolymerization
Williams Syndrome
Rho
PAK3 (p21 Activated Kinase)
JNK p38
Cytoskeletonraf-1LTD disruption?
Dbl (Diffuse B-cell Lymphoma)Rho GEF6
Rho GAPRho GDI
GEFs+ _
Nonsyndromic X-Linked Mental Retardation