Fragile X-associated tremor/ataxia syndrome (FXTAS) is a leading monogenic neurodegenerative disorder affecting premutation carriers of the fragile X (FMR1) gene. To investigate the underlying cellular neuropathology, we produced induced pluripotent stem cell-derived neurons from isogenic subclones of primary fibroblasts of a female premutation carrier, with each subclone bearing exclusively either the normal or the expanded (premutation) form of the FMR1 gene as the active allele. We show that neurons harboring the stably-active, expanded allele (EX-Xa) have reduced postsynaptic density protein 95 protein expression, reduced synaptic puncta density and reduced neurite length. Importantly, such neurons are also functionally abnormal, with calcium transients of higher amplitude and increased frequency than for neurons harboring the normal-active allele. Moreover, a sustained calcium elevation was found in the EX-Xa neurons after glutamate application. By excluding the individual genetic background variation, we have demonstrated neuronal phenotypes directly linked to the FMR1 premutation. Our approach represents a unique isogenic, X-chromosomal epigenetic model to aid the development of targeted therapeutics for FXTAS, and more broadly as a model for the study of common neurodevelopmental (e.g. autism) and neurodegenerative (e.g. Parkinsonism, dementias) disorders.
"Unlike females with FXTAS, the PD patients did not have increased N400 activity to semantically congruous words. The pathophysiological basis of the abnormal N400 congruity effect in FXTAS females could be the FMR1 mRNAmediated glutamatergic abnormalities found both in fragile X premutation mouse models (Cao et al. 2012; Hunsaker et al. 2012) and in induced pluripotent stem cell-derived human neurons harboring the premutation expansion (Liu et al. 2012). Using a picture recognition paradigm, depth recording studies in the anteromedial temporal lobe found that the N400 amplitude was modulated/reduced by the NMDA glutamate receptor antagonist ketamine (Grunwald et al. 1999). "
[Show abstract][Hide abstract] ABSTRACT: FXTAS, a neurodegenerative disorder, affects Fragile X (FMR1) gene premutation carriers in late-life. Studies have shown cognitive impairments in FXTAS including executive dysfunction, working memory, and visuospatial deficits. However, less is known about cognition in females with FXTAS. Thus, we examined semantic processing and verbal memory in female FXTAS patients with event-related potentials (ERPs) and neuropsychological testing. 61 females (34 FXTAS Mage = 62.7, 27 controls Mage = 60.4) were studied with 32-channel ERPs during a category judgment task in which semantically congruous (50%) and incongruous items were repeated ~10-140s later. N400 and P600 amplitude data were submitted to ANCOVA. Neuropsychological testing demonstrated lower performance in verbal learning and executive function in females with FXTAS. ERP analyses revealed a significant reduction of the N400 congruity effect (incongruous - congruous) in the FXTAS group. The N400 congruity effect reduction in females with FXTAS was mainly due to increased N400 amplitude to congruous new words. No significant abnormalities of the N400 repetition effect or the P600 repetition effect were found, indicating preserved implicit memory and verbal memory, respectively, in females with FXTAS. The decreased N400 congruity effect suggests abnormal semantic expectancy and/or semantic network disorganization in female FXTAS patients. The enhanced N400 amplitude to congruous new words may reflect decreased cognitive flexibility among FXTAS women, making access to less typical category exemplar words more difficult.
"Recent evidence points to abnormalities in glutamatergic signaling in the FMR1 CGG knock-in (KI) mouse model of PM (PreCGG) (Cao et al., 2012) and in the induced pluripotent stem cell (iPSC) derived human PM neurons from human fibroblast (Liu et al., 2012). Alterations in Glu uptake kinetics and augmented group I metabotropic Glu receptors (Gp1 mGluRs: mGluR1 and mGluR5) activity observed in preCGG neurons suggests that a defect in Glu transport and signaling in astrocytes could also contribute to PM pathology (Cao et al., 2012), and is consistent with results from a more recent study indicating that astrocytic cultures from frontal cortex of preCGG mice have altered asynchronous Ca 2þ oscillations and glutamatergic responses associated with modest reductions of both GLT1 and GLAST expression (Cao et al., 2013). "
[Show abstract][Hide abstract] ABSTRACT: A premutation (PM) expansion (55-200 CGG) in the fragile X mental retardation gene 1 causes elevated messenger RNA and reduced fragile X mental retardation gene 1 protein. Young PM carriers can develop characteristic physical features and mild cognitive disabilities. In addition, individuals with PM, particularly male carriers, are at high risk to develop fragile X-associated tremor/ataxia syndrome (FXTAS) with aging. Human postmortem FXTAS brains show extensive white matter disease in the cerebellum and the presence of intranuclear inclusions throughout the brain, although their etiologic significance is unknown. In the current work, expression levels of the metabotropic glutamate (Glu) receptor 5 and the Glu transporter excitatory amino acid transporter 1, examined by reverse transcription polymerase chain reaction and western blot analyses, were found to be reduced in the postmortem cerebellum of PM carriers with FXTAS compared with age matched controls, with higher CGG repeat number having greater reductions in both proteins. These data suggests a dysregulation of Glu signaling in PM carriers, which would likely contribute to the development and severity of FXTAS.
Neurobiology of aging 11/2013; 35(5). DOI:10.1016/j.neurobiolaging.2013.11.009 · 5.01 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Human neurons, generated from reprogrammed somatic cells isolated from live patients, bring a new perspective on the understanding of Autism Spectrum Disorders (ASD). The new technology can nicely complement other models for basic research and the development of therapeutic compounds aiming to revert or ameliorate the condition. Here, we discuss recent advances on the use of stem cells and other models to study ASDs, as well as their limitations, implications and future perspectives.
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