Date of Completion

9-7-2017

Embargo Period

9-7-2017

Keywords

FXTAS, FXPOI, FXS, RNA, granule, CGG repeat, translation, premutation, PKR, calcium

Major Advisor

Dr. John H. Carson

Associate Advisor

Dr. Elisa Barbarese

Associate Advisor

Dr. Ann Cowan

Associate Advisor

Dr. Michael Blinov

Field of Study

Biomedical Science

Degree

Doctor of Philosophy

Open Access

Open Access

Abstract

Fragile X tremor ataxia syndrome (FXTAS) and fragile X primary ovarian insufficiency (FXPOI) are associated with CGG repeat expansions in the 5’UTR of the FMR1 gene. RNAs containing an hnRNP A2 response element (A2RE) are localized and transported in hnRNP A2 granules that are organized by multivalent interactions. We show that RNAs containing CGG repeats are also localized in hnRNP A2 granules. Exogenous expanded CGG repeat RNA microinjected in mouse hippocampal neurons or oocytes inhibits granule RNA translation. Endogenous premutation CGG repeats in FMR1 in human fibroblast cells from females at risk for FXPOI also inhibit granule RNA translation. We suggest that CGG repeat RNAs encoding calcium regulatory proteins may be in RNA granules and show that CGG repeat RNAs in premutation human fibroblast cells affect calcium homeostasis which may contribute to FXTAS and FXPOI pathogenesis. Premutation CGG repeat RNA containing the 5’UTR and part of the FMR1 ORF and intron 1 in the transgenic TG296 mouse does not inhibit granule RNA translation. We suggest that FXTAS and FXPOI are granule based phenomena and RNA gain of function disorders. We suggest two mechanisms for RNA gain of function mechanisms, sequestration of translational machinery and activation of the double stranded binding protein, protein kinase R (PKR). Differences in the magnitude of translational inhibition by CGG repeat RNA in neurons, fibroblasts and oocytes suggests that activation of PKR is most likely the pathogenic mechanism for FXTAS and FXPOI.

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