Effects of FMRP loss on dendritic and somatic translation in CA1 pyramidal neurons during memory storage
Barakatalroudaini, Yehya.
2019
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Fragile X Syndrome is
a common inherited monogenetic disorder caused by the epigenetic silencing of the Fmr1
gene located on the X chromosome. The disorder causes cognitive deficits, physical
malformations, autistic behavior, and audio-sensitive epilepsy. Despite much research on
the pathophysiology of Fragile X Syndrome, there is still no cure. Fragile X Mental
Retardation Protein (FMRP), ... read morethe protein product of the Fmr1 gene, is an RNA binding
protein with the ability to repress translation of select mRNAs. FMRP also regulates the
initiation of translation through its interaction with elongation initiation factors. To
better understand the impact of FMRP loss on mRNA translation in neurons, we used an
Fmr1 knockout mouse line that expresses EGFP-tagged ribosomes in hippocampal CA1
pyramidal neurons. By combining tissue microdissection with Translating Ribosome
Affinity Purification (TRAP), we could selectively isolate mRNA that was bound to
EGFP-tagged ribosomes in either the dendrites or soma of CA1 pyramidal neurons.
Sequencing of this mRNA indicated that FMRP loss has different effects on mRNA
associated with ribosomes in dendrites versus soma. In addition, these differential
effects on dendritic and somatic translation depended on the activation history of the
CA1 pyramidal neurons, which we determined by comparing mice that were resting in their
home cage with mice that were subjected to a memory test known as contextual fear
conditioning. Our results provide a proof of concept for using TRAP to study local
translation changes in a Fragile X Syndrome mouse model, and possibly relate FMRP loss
with altered somatic translation during the acquisition of a
memory.
Thesis (M.S.)--Tufts University, 2019.
Submitted to the Dept. of Pharmacology and Drug Development.
Advisor: Leon Reijmers.
Keywords: Neurosciences, Genetics, and Bioinformatics.read less - ID:
- hm50v5203
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