Novel role of Cdh1-APC as a regulator of neuronal protein synthesis and stress granule dynamics Open Access

Lai, Austin (Spring 2020)

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Protein homeostasis, the balance between protein synthesis and degradation, is crucial to synaptic function and long-term synaptic modifications. Dysregulated protein homeostasis can therefore lead to defects in learning and memory, as seen in the neurodevelopmental disorder Fragile X Syndrome (FXS)—the most prevalent form of inherited intellectual disability. FXS is caused by the loss of Fragile X Mental Retardation protein (FMRP) and the excess protein synthesis that results. Previously observed dysregulation of the ubiquitin-proteasome system (UPS) in related neurodevelopmental disorders suggests the possible involvement of dysregulated ubiquitination in FXS. Furthermore, the E3 ligase complex Cdh1-APC has been shown to associate with FMRP in vivo. However, the interaction of the APC coactivator Cdh1 with FMRP and the consequences of such an interaction remain unclear. We hypothesized that Cdh1-APC downregulates FMRP through interaction with the destruction (D)-box domain and promotes protein synthesis. Here, we show that the interaction of FMRP with Cdh1 affects the protein expression of FMRP. Using FMRP mutants, we demonstrate that mutation in the D-box motif sequence and lysine residues of the Fmr1 gene results in higher levels of FMRP protein expression, and a lower steady-state protein synthesis.

Additionally, unpublished studies from our lab showed that Cdh1 interacts with multiple stress granule-associated proteins, suggesting that stress granule dynamics may be regulated by the Cdh1-APC-mediated ubiquitination of FMRP. Stress granules are membrane-less organelles comprised of translationally repressed mRNAs and ribonucleoproteins. We hypothesized that Cdh1-APC regulates stress granule dynamics through its regulation of FMRP. We show that ubiquitination by Cdh1-APC reduces the assembly of stress granules in an FMRP-dependent manner. We further show that stimulation of group 1 metabotropic glutamate receptor reduces stress granule formation. Altogether, these results clarify the role of Cdh1-APC as a neuronal translational regulator and a potential target for Fragile X Syndrome.

Table of Contents

Introduction 1

Methods 19

Results 27

Discussion 38

References 43

Figures 51

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