Cdh1-APC Regulates Protein Synthesis and Stress Granules in Neurons through an FMRP-Dependent Mechanism

Valdez‐Sinon, Arielle N.; Lai, Austin; Shi, Liang; Lancaster, Carly L.; Gokhale, Avanti; Faundez, Victor; Bassell, Gary J.

doi:10.1016/j.isci.2020.101132

Cited by 24 publications

(27 citation statements)

References 54 publications

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“… Peptides enriched two-fold compared to negative control can undergo DAVID Analysis ( https://david.ncifcrf.gov ) to categorize the interactome based on gene ontology. In previous publications, the DAVID analysis was run with medium classification stringency and threshold p value of < 0.005 ( Valdez-Sinon et al., 2020 ). For additional guidance on DAVID analysis and selecting parameters, utilize the following references: Huang et al, 2007 , Huang et al, 2009 .…”

Section: Step-by-step Methods Detailsmentioning

confidence: 99%

“…In previous publications, the DAVID analysis was run with medium classification stringency and threshold p value of < 0.005 ( Valdez-Sinon et al., 2020 ).…”

Section: Step-by-step Methods Detailsmentioning

confidence: 99%

“…This protocol was used in a recent publication ( Valdez-Sinon et al., 2020 ) to isolate and identify the interactome of a protein known as Cdh1 (Fzr1) for which we hypothesized to play a role in RNA granules and protein synthesis. The results yielded an enrichment of ribonucleoprotein complexes with 36.7% of the interactome being associated with translation function and regulation.…”

Section: Before You Beginmentioning

confidence: 99%

“…Gene ontology analyses performed following mass spectrometry-based proteomics may elucidate novel functions of proteins of interest. For complete details on the use and application of this protocol, please refer to Valdez-Sinon et al. (2020) .…”

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confidence: 99%

“…For complete details on the use and application of this protocol, please refer to Valdez-Sinon et al. (2020) .…”

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confidence: 99%

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Protocol for Immuno-Enrichment of FLAG-Tagged Protein Complexes

et al. 2020

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Summary This protocol describes immunoprecipitation of proteins associated with FLAG-tagged recombinant proteins followed by mass spectrometry-based proteomics to identify the associated interactome components. FLAG epitope was chosen, because existing high-affinity monoclonal antibodies allow for sensitive immunoprecipitation and FLAG peptides permit efficient elution of protein complexes. With many commercially available FLAG tools, this protocol is highly versatile. This procedure reduces immunoprecipitation of nonspecific binding proteins. Gene ontology analyses performed following mass spectrometry-based proteomics may elucidate novel functions of proteins of interest. For complete details on the use and application of this protocol, please refer to Valdez-Sinon et al. (2020) .

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Section: Step-by-step Methods Detailsmentioning

confidence: 99%

“…In previous publications, the DAVID analysis was run with medium classification stringency and threshold p value of < 0.005 ( Valdez-Sinon et al., 2020 ).…”

Section: Step-by-step Methods Detailsmentioning

confidence: 99%

Section: Before You Beginmentioning

confidence: 99%

mentioning

confidence: 99%

“…For complete details on the use and application of this protocol, please refer to Valdez-Sinon et al. (2020) .…”

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confidence: 99%

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Protocol for Immuno-Enrichment of FLAG-Tagged Protein Complexes

et al. 2020

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Amyloid beta induces Fmr1‐dependent translational suppression and hyposynchrony of neural activity via phosphorylation of eIF2α and eEF2

Lizarazo

Yook

Tsai

2022

Journal Cellular Physiology

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Alzheimer's disease (AD) is the most common cause of dementia, with the accumulation of amyloid beta peptide (Aβ) being one of the main causes of the disease. Fragile X mental retardation protein (FMRP), encoded by fragile X mental retardation 1 (Fmr1), is an RNA‐binding protein that represses translation of its bound mRNAs or exerts other indirect mechanisms that result in translational suppression. Because the accumulation of Aβ has been shown to cause translational suppression resulting from the elevated cellular stress response, in this study we asked whether and how Fmr1 is involved in Aβ‐induced translational regulation. Our data first showed that the application of synthetic Aβ peptide induces the expression of Fmr1 in cultured primary neurons. We followed by showing that Fmr1 is required for Aβ‐induced translational suppression, hyposynchrony of neuronal firing activity, and loss of excitatory synapses. Mechanistically, we revealed that Fmr1 functions to repress the expression of phosphatases including protein phosphatase 2A (PP2A) and protein phosphatase 1 (PP1), leading to elevated phosphorylation of eukaryotic initiation factor 2‐α (eIF2α) and eukaryotic elongation factor 2 (eEF2), and subsequent translational suppression. Finally, our data suggest that such translational suppression is critical to Aβ‐induced hyposynchrony of firing activity, but not the loss of synapses. Altogether, our study uncovers a novel mechanism by which Aβ triggers translational suppression and we reveal the participation of Fmr1 in altered neural plasticity associated with Aβ pathology. Our study may also provide information for a better understanding of Aβ‐induced cellular stress responses in AD.

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Amyotrophic Lateral Sclerosis-Related Gene Interactions with Fat Mass and Obesity-Associated Gene

Kadena

Skolariki

Vlachakis

et al. 2023

Handbook of Computational Neurodegeneration

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Cdh1-APC Regulates Protein Synthesis and Stress Granules in Neurons through an FMRP-Dependent Mechanism

Abstract: Inhibition of Cdh1-APC decreases protein synthesis in cortical neurons Cdh1 interacts with translational machinery including stress granule proteinsCdh1-APC regulates the formation of stress granules in neurons through FMRP Cdh1-APC has a dual role in protein homeostasis

Cited by 24 publications

References 54 publications

Protocol for Immuno-Enrichment of FLAG-Tagged Protein Complexes

Protocol for Immuno-Enrichment of FLAG-Tagged Protein Complexes

Amyloid beta induces Fmr1‐dependent translational suppression and hyposynchrony of neural activity via phosphorylation of eIF2α and eEF2

Amyotrophic Lateral Sclerosis-Related Gene Interactions with Fat Mass and Obesity-Associated Gene

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