Date of Degree

2-2016

Document Type

Dissertation

Degree Name

Ph.D.

Program

Biochemistry

Advisor(s)

Paul Feinstein

Committee Members

Mitchell Goldfarb

Carmen Melendez-Vasquez

Jonathan Levitt

Robert H. Singer

Subject Categories

Biochemistry | Molecular and Cellular Neuroscience | Molecular Biology

Keywords

autism, Fragile X Syndrome, FMRP, neuron, RNA, Neuroligin

Abstract

Fragile X Syndrome (FXS) is one of the most commonly inherited mental retardations. It is caused by the loss of functional fragile X mental retardation protein (FMRP). Loss of functional FMRP is the most widespread single-gene cause of autism. The most prominent phenotype of FXS patients is an IQ ranging from 20 to 70. FMRP is an RNA binding protein, widely expressed in almost all tissues and highly expressed in brain. As a RNA binding protein, 85-90 % of FMRP in the brain is associated with polyribosomes. Approximately 4 % of total mRNA is associated with FMRP, which functions in the stability, transport and translational regulation of its targeted mRNAs.

The 3’ untranslated region (3’UTR) of mRNAs can be important for their subcellular localization and translational regulation. Many genes contain localization elements in their 3’UTRs that enable transcripts to localize to dendrites for site-specific translation. FMRP functions as a translational regulator in this process.

Local translation of certain proteins is crucial to synaptic plasticity. Synaptic plasticity is the ability of a synapse to regulate its strength over time in response to stimuli. It is the basis of learning and memory. The two forms of long-term plasticity are long-term depression (LTD) and long-term potentiation (LTP). FXS patients and Fmr1KOmice all show exaggerated LTD in the hippocampus, which is the center of emotion, memory, and the autonomic nervous system. In addition, some types of abnormal LTP have been demonstrated in Fmr1KOmice. These evidences indicate that FMRP plays an important role in synaptic plasticity through translational regulation of target mRNAs.

Neuroligin (NL) is a family of neural adhesion molecules. Neuroligins are trans-membrane proteins located at the post-synaptic membrane and bind with pre-synaptic adhesion molecules known as NEUREXIN (NRX). Neuroligins function in synaptogenesis, synapse differentiation, and synapse maintenance. Importantly, they have been shown to be involved in autism and other cognitive diseases.

Both neuroligins and neurexins are products of alternative splicing. The recognition between neuroligins and neurexins is splice variant-dependent. This variant-specific binding triggers different downstream signals for synaptogenesis and synapse differentiation. The work presented here addresses the targeting of FMRP to the 3’ UTR of some dendritic mRNAs and their translational regulation. And for the first time, we demonstrate that FMRP is involved in the alternative splicing of mRNA. FRMP is found related to Neuroligin1 splicing in mice hippocampus.

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