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

Simon Lizarazo, Yeeun Yook, Nien Pei Tsai

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2929-2942
Number of pages14
JournalJournal of Cellular Physiology
Volume237
Issue number7
DOIs
StatePublished - Jul 2022

Keywords

  • Fmr1
  • PP1
  • PP2A
  • eEF2
  • eIF2α
  • translation

ASJC Scopus subject areas

  • Physiology
  • Clinical Biochemistry
  • Cell Biology

Fingerprint

Dive into the research topics of 'Amyloid beta induces Fmr1-dependent translational suppression and hyposynchrony of neural activity via phosphorylation of eIF2α and eEF2'. Together they form a unique fingerprint.

Cite this