Altered mTOR signaling and enhanced CYFIP2 expression levels in subjects with fragile X syndrome

C. A. Hoeffer, E. Sanchez, R. J. Hagerman, Y. Mu, D. V. Nguyen, H. Wong, A. M. Whelan, R. Suzanne Zukin, E. Klann, F. Tassone

Research output: Contribution to journalArticle

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Abstract

Fragile X syndrome (FXS) is the most common form of inherited intellectual disability and autism. The protein (FMRP) encoded by the fragile X mental retardation gene (FMR1), is an RNA-binding protein linked to translational control. Recently, in the Fmr1 knockout mouse model of FXS, dysregulated translation initiation signaling was observed. To investigate whether an altered signaling was also a feature of subjects with FXS compared to typical developing controls, we isolated total RNA and translational control proteins from lymphocytes of subjects from both groups (38 FXS and 14 TD). Although we did not observe any difference in the expression level of messenger RNAs (mRNAs) for translational initiation control proteins isolated from participant with FXS, we found increased phosphorylation of the mammalian target of rapamycin (mTOR) substrate, p70 ribosomal subunit 6 kinase1 (S6K1) and of the mTOR regulator, the serine/threonine protein kinase (Akt), in their protein lysates. In addition, we observed increased phosphorylation of the cap binding protein eukaryotic initiation factor 4E (eIF4E) suggesting that protein synthesis is upregulated in FXS. Similar to the findings in lymphocytes, we observed increased phosphorylation of S6K1 in brain tissue from patients with FXS (n = 4) compared to normal age-matched controls (n = 4). Finally, we detected increased expression of the cytoplasmic FMR1-interacting protein 2 (CYFIP2), a known FMRP interactor. This data verify and extend previous findings using lymphocytes for studies of neuropsychiatric disorders and provide evidence that misregulation of mTOR signaling observed in the FXS mouse model also occurs in human FXS and may provide useful biomarkers for designing targeted treatments in FXS.

Original languageEnglish (US)
Pages (from-to)332-341
Number of pages10
JournalGenes, Brain and Behavior
Volume11
Issue number3
DOIs
StatePublished - Apr 2012

Fingerprint

Fragile X Syndrome
Sirolimus
Proteins
Phosphorylation
Lymphocytes
Intellectual Disability
Translational Peptide Chain Initiation
RNA Cap-Binding Proteins
Fragile X Mental Retardation Protein
Eukaryotic Initiation Factor-4E
Ribosome Subunits
RNA-Binding Proteins
Protein-Serine-Threonine Kinases
Autistic Disorder
Knockout Mice
Biomarkers
RNA

Keywords

  • CYFIP1
  • CYFIP2
  • Fragile X
  • MTOR
  • Phosphorylation

ASJC Scopus subject areas

  • Behavioral Neuroscience
  • Genetics
  • Neurology

Cite this

Hoeffer, C. A., Sanchez, E., Hagerman, R. J., Mu, Y., Nguyen, D. V., Wong, H., ... Tassone, F. (2012). Altered mTOR signaling and enhanced CYFIP2 expression levels in subjects with fragile X syndrome. Genes, Brain and Behavior, 11(3), 332-341. https://doi.org/10.1111/j.1601-183X.2012.00768.x

Altered mTOR signaling and enhanced CYFIP2 expression levels in subjects with fragile X syndrome. / Hoeffer, C. A.; Sanchez, E.; Hagerman, R. J.; Mu, Y.; Nguyen, D. V.; Wong, H.; Whelan, A. M.; Zukin, R. Suzanne; Klann, E.; Tassone, F.

In: Genes, Brain and Behavior, Vol. 11, No. 3, 04.2012, p. 332-341.

Research output: Contribution to journalArticle

Hoeffer, CA, Sanchez, E, Hagerman, RJ, Mu, Y, Nguyen, DV, Wong, H, Whelan, AM, Zukin, RS, Klann, E & Tassone, F 2012, 'Altered mTOR signaling and enhanced CYFIP2 expression levels in subjects with fragile X syndrome', Genes, Brain and Behavior, vol. 11, no. 3, pp. 332-341. https://doi.org/10.1111/j.1601-183X.2012.00768.x
Hoeffer, C. A. ; Sanchez, E. ; Hagerman, R. J. ; Mu, Y. ; Nguyen, D. V. ; Wong, H. ; Whelan, A. M. ; Zukin, R. Suzanne ; Klann, E. ; Tassone, F. / Altered mTOR signaling and enhanced CYFIP2 expression levels in subjects with fragile X syndrome. In: Genes, Brain and Behavior. 2012 ; Vol. 11, No. 3. pp. 332-341.
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