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Regulation of Translation and Synaptic Plasticity by TSC2 University of Massachusetts Medical School eScholarship@UMMS GSBS Dissertations and Theses Graduate School of Biomedical Sciences 2020-07-22 Regulation of Translation and Synaptic Plasticity by TSC2 Annie Hien University of Massachusetts Medical School Let us know how access to this document benefits ou.y Follow this and additional works at: https://escholarship.umassmed.edu/gsbs_diss Part of the Molecular and Cellular Neuroscience Commons Repository Citation Hien A. (2020). Regulation of Translation and Synaptic Plasticity by TSC2. GSBS Dissertations and Theses. https://doi.org/10.13028/zhjn-x778. Retrieved from https://escholarship.umassmed.edu/ gsbs_diss/1097 Creative Commons License This work is licensed under a Creative Commons Attribution-Noncommercial 4.0 License This material is brought to you by eScholarship@UMMS. It has been accepted for inclusion in GSBS Dissertations and Theses by an authorized administrator of eScholarship@UMMS. For more information, please contact [email protected]. i REGULATION OF TRANSLATION AND SYNAPTIC PLASTICITY BY TSC2 A Dissertation Presented By ANNIE HIEN Submitted to the Faculty of the University of Massachusetts Graduate School of Biomedical Sciences, Worcester in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY July 22th, 2020 Molecular Neuroscience i ii REGULATION OF TRANSLATION AND SYNAPTIC PLASTICITY BY TSC2 A Dissertation Presented By ANNIE HIEN This work was undertaken in the Graduate School of Biomedical Sciences M.D./Ph.D. Program Under the mentorship of ____________________________________________________ Joel Richter, Ph.D., Thesis Advisor ____________________________________________________ Daryl Bosco, Ph.D., Member of Committee ____________________________________________________ Erik Sontheimer, Ph.D., Member of Committee ____________________________________________________ Craig Peterson, Ph.D., Member of Committee ____________________________________________________ Elizabeth Gavis, M.D./Ph.D., External Member of Committee ____________________________________________________ Andrei Korostelev, Ph.D., Chair of Committee ____________________________________________________ Mary Ellen Lane, Ph.D. Dean of the Graduate School of Biomedical Sciences July 22th, 2020 ii iii ACKNOWLEDGEMENTS My thesis work would not be possible without the unwavering encouragement and guidance of my mentor, Dr. Joel Richter. Joel encourages me to think outside the box, explore my scientific curiosities, foster collaborations with others, and has improved my writing and vocabulary with phrases such as “not a big hairy deal”. Most importantly, Joel taught me to be bold scientist (and person) with a voice. I am forever grateful for his dedication to my professional development. My thesis project would also not be possible without my excellent collaborators, Drs. Gemma Molinaro and Kimberly Huber from the University of Texas Southwestern- this project took a heroic effort on everyone’s part. Current and former members of the Richter lab have been invaluable for intellectual discussions, moral support, and mentorship- I could not ask for better colleagues from Drs. Lori Lorenz, Maria Ivshina, Huan (Raya) Shu, Sneha Shah, Heleen van't Spijker, Suna Jung, and fellow student Mohamad Nasrallah. In particular, Drs. Botao Liu for contributing to my thesis project and teaching me ribosome profiling and the associated analysis, Emily Stackpole for teaching how to perform sucrose gradients and intellectual discussions related to FXR2P, Rhonda McFleder for being a mentor while I rotated in the lab and onward, and Ruijia (Ray) Wang for help with bioinformatics analysis. I would like to thank members of my TRAC for their guidance and input over the years, Drs. Andrei Korostelev, Daryl Bosco, Erik Sontheimer, and Lihua (Julie) Zhu. I am also grateful for Dr. Craig Peterson at UMass and Dr. Elizabeth Gavis at Princeton University for reviewing my thesis and serving on my Defense Exam Committee. iii iv I have been supported on this current career trajectory by the delicious home cooked meals and the enormous sacrifices made by my parents, Ying and Thuy, who immigrated to the USA without knowing English to provide better opportunities for my sisters and me. Through leading by example, you have instilled in me a diligent work ethics and resilience. For my community outside of lab, I want to thank my three sisters Amy, Winnie, and Jessica, my friends at UMass, from Malden, the Kingdom Trail group, and climbing crew- you have all kept me sane and happy. Finally, I want to acknowledge my favorite climbing, biking, and life partner, Eric. I am grateful for your constant love and support through the sunny and cloudy days of the MD/PhD path. I look forward to our post-UMass adventures with our cats (hopefully more to come). iv v ABSTRACT Mutations in TSC2 cause the disorder tuberous sclerosis (TSC), which has a high incidence of autism and intellectual disability. TSC2 regulates mRNA translation required for group 1 metabotropic glutamate receptor-dependent synaptic long-term depression (mGluR-LTD), but the identity of mRNAs responsive to mGluR-LTD signaling in the normal and TSC brain is largely unknown. We generated Tsc2+/- mice to model TSC autism and performed ribosome profiling to identify differentially expressed genes following mGluR-LTD in the normal and Tsc2+/- hippocampus. Ribosome profiling reveals that in Tsc2+/- mice, RNA-binding targets of Fragile X Mental Retardation Protein (FMRP) are increased. In wild-type hippocampus, induction of mGluR-LTD caused rapid changes in the steady state levels of hundreds of mRNAs, many of which are FMRP targets. Moreover, mGluR-LTD signaling failed to promote phosphorylation of eukaryotic elongation factor 2 (eEF2) in Tsc2+/- mice, and chemically mimicking phospho-eEF2 with low cycloheximide enhances mGluR-LTD in the Tsc2+/- brain. These results suggest a molecular basis for bidirectional regulation of synaptic plasticity by TSC2 and FMRP. Furthermore, deficient mGluR-regulated translation elongation contributes to impaired synaptic plasticity in Tsc2+/- mice. v vi TABLE OF CONTENTS Reviewer page .................................................................................................................... ii Acknowledgements ........................................................................................................... iii Abstract .............................................................................................................................. v Table of Contents ............................................................................................................. vi List of Figures ................................................................................................................... ix List of Tables ..................................................................................................................... xi Glossary of Terms .......................................................................................................... xii Chapter I Introduction ..................................................................................................... 1 Overview of tuberous sclerosis .................................................................................................. 1 Clinical features of tuberous sclerosis ..................................................................................... 1 Genetics of tuberous sclerosis ................................................................................................. 2 TSC is an inhibitor of mTOR signaling ................................................................................... 3 Neurological functions of TSC ................................................................................................ 5 Treatment options for TSC ...................................................................................................... 6 Overview of Fragile X Syndrome ............................................................................................. 7 Genetics of Fragile X Syndrome ............................................................................................. 7 Clinical features of Fragile X Syndrome ................................................................................. 8 Molecular function of FMRP ................................................................................................... 8 Treatment options for FXS ...................................................................................................... 9 Protein homeostasis in synaptic plasticity ............................................................................... 9 Optimal neural performance depends on protein homeostasis ................................................ 9 Some forms of memory require rapid protein synthesis ........................................................ 10 Synaptic plasticity depends on local, activity-dependent translation in neurons .................. 12 Translational regulation in synaptic plasticity ...................................................................... 13 vi vii Regulators of translation initiation in synaptic plasticity ...................................................... 13 Regulation of translation elongation in synaptic plasticity .................................................... 21 Convergence of mGluR5 and mTOR signaling on ASD ....................................................... 23 Chapter II Ribosome Profiling
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