Altered hypothalamus–pituitary–adrenal gland axis regulation in the expanded CGG-repeat mouse model for fragile X-associated tremor/ataxia syndrome

Abstract

The human FMR1 gene contains an unstable CGG-repeat in its 5′ untranslated region. The repeat length in the normal population is polymorphic (5-54 CGG-repeats). Individuals carrying lengths beyond 200 CGGs (i.e. the full mutation) show hypermethylation and as a consequence gene silencing of the FMR1 gene. The absence of the gene product FMRP causes the fragile X syndrome, the most common inherited form of mental retardation. Elderly carriers of the premutation (PM), which is defined as a repeat length between 55-200 CGGs, can develop a progressive neurodegenerative syndrome: fragile X-associated tremor/ataxia syndrome (FXTAS). The high FMR1 mRNA levels observed in cells from PM carriers have led to the hypothesis that FXTAS is caused by a pathogenic RNA gain-of-function mechanism. Apart from tremor/ataxia, specific psychiatric symptoms have been described in PM carriers with or without FXTAS. Since these symptoms could arise from elevated stress hormone levels, we investigated hypothalamicpituitary-adrenal (HPA) axis regulation using a knock-in mouse model with an expanded CGGrepeat in the PM range (>98 repeats) in the Fmr1 gene, which shows repeat instability, and displays biochemical, phenotypic and neuropathological characteristics of FXTAS. We show elevated levels of corticosterone in serum and ubiquitin-positive inclusions in both the pituitary and adrenal gland of 100-week old animals. In addition, we demonstrate ubiquitin-positive © 2008 Elsevier Ltd. All rights reserved. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Financial disclosuresWe declare no conflict of interest. HHS Public Access Author Manuscript Author ManuscriptAuthor ManuscriptAuthor Manuscript inclusions in the amygdala from aged expanded CGG-repeat mice. We hypothesize that altered regulation of the HPA axis and the amygdala and higher stress hormone levels in the mouse model for FXTAS may explain associated psychological symptoms in humans.

Ovarian Abnormalities in a Mouse Model of Fragile X Primary Ovarian Insufficiency

“…The reduced level of FMRP in PM carriers is thought to reflect the inhibitory effect of long CGG-repeats on translation (Feng et al 1995). In human and murine carriers of PM alleles, intranuclear inclusions containing FMR1 mRNA are seen in a number of non-ovarian cell types, including those of the brain and adrenal glands (Brouwer et al 2008). However, we observed only one acidophilic nuclear inclusion in an oocyte of 1 of 45 PM mice examined and no inclusions at all in other ovarian cells.…”

Immune‐mediated disorders among women carriers of fragile X premutation alleles

“…The FMR1 premutation leads to dysregulation of the HPA axis, leading in turn to enhanced release of the stress hormone cortisol, as demonstrated in the premutation mouse [Brouwer et al, 2008]. Cortisol dysregulation and stress can lead to inflammation and activation of the immune system [Chang et al, 2009].…”

Fragile X: Leading the Way for Targeted Treatments in Autism

“…43–45 Premutation knock in mice have been created and they demonstrate enhanced cortisol release with stress compared to controls without the premutation. 46 As we translate this information to human carriers there is often significant stress because of raising children with FXS and participation in the care of a parent who may be suffering from FXTAS. In female carriers higher levels of anxiety, as measured by the SCL-90, correlate with more atrophy in the hippocampus.…”