Download William Greenough: Role of FMRP in Protein Synthesis

William Greenough: Role of FMRP in Protein Synthesis
Silencing of the gene encoding the fragile X mental retardation protein (FMRP) is the
cause of the most common inherited mental retardation. FMRP binds a substantial
number of mRNAs, including its own, and appears to bind at least some of them in the
nucleus and to accompany them in ribonucleoprotein granules transported along dendrites
in a kinesin1-dynein-microtubule-dependent manner. Transport to dendrites is enhanced
by depolarization or glutamate activation. The transported messages encode proteins with
a broad variety of cellular roles. FMRP, a significant amount of which is associated with
the polysome fraction, regulates their translation and this in turn appears to be regulated
for at least some proteins by group 1 mGluR activation at synapses. Receptor activation
triggers rapid initiation of translation for at least some proteins. This rapid initiation is
disrupted in the Fmr1-null mouse. The neuronal phenotype of the fragile X syndrome
includes immature-appearing synapses and an excess of synapses and of dendritic
material in cortical and hippocampal regions examined. This suggests a model in which
FMRP may selectively target specific messages to activated synapses whereas those same
messages may be uniformly distributed in FMRP’s absence.
Recent reference:
Weiler IJ, Spangler CC, Klintsova AY, Grossman AW, Kim SH, Bertaina-Anglade V,
Khaliq H, de Vries FE, Lambers FA, Hatia F, Base CK, Greenough WT. From the Cover:
Fragile X mental retardation protein is necessary for neurotransmitter-activated protein
translation at synapses. Proc Natl Acad Sci U S A. 2004,101:17504-9.