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Carriers of the fragile X mental retardation 1 (FMR1) premutation allele present with increased levels of cytokine IL-10.

ABSTRACT: BACKGROUND: Fragile X-associated tremor/ataxia syndrome (FXTAS) is an inherited late-onset neurodegenerative disorder, characterized both by neurological and cognitive deficits. It is caused by the expansion of CGG repeats (55 to 200 repeats) in the noncoding region of the fragile X mental retardation 1 (FMR1) gene. Abnormal immunological patterns are often associated with neurodegenerative disorders and implicated in their etiology. We therefore investigated the immune status of FXTAS patients, which had not been assessed prior to this study. METHOD: Peripheral blood mononuclear cells (PBMCs) were collected from 15 asymptomatic FMR1 premutation carriers and 20 age-matched controls. Concentrations of three cytokines (IL-6, IL-8, IL-10) were measured in PBMC supernatants using ELISA assays. RESULTS: We found a significant increase in the concentration of the major anti-inflammatory cytokine IL-10 in supernatants of PBMCs derived from premutation carriers, when compared with controls (P = 0.019). This increase correlated significantly with the number of CGG repeats (P = 0.002). CONCLUSIONS: Elevated IL-10 levels were observed in all premutation carriers, before appearance of the classical neurological symptoms; therefore, IL-10 may be one of the early biomarkers of FXTAS.

SUBMITTER: Marek D

PROVIDER: S-EPMC3528457 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Carriers of the fragile X mental retardation 1 (FMR1) premutation allele present with increased levels of cytokine IL-10.

Marek Diana D Papin Stephanie S Ellefsen Kim K Niederhauser Julien J Isidor Nathalie N Ransijn Adriana A Poupon Lucienne L Spertini Francois F Pantaleo Giuseppe G Bergmann Sven S Beckmann Jacques S JS Jacquemont Sebastien S Tanackovic Goranka G

Journal of neuroinflammation 20121013

<h4>Background</h4>Fragile X-associated tremor/ataxia syndrome (FXTAS) is an inherited late-onset neurodegenerative disorder, characterized both by neurological and cognitive deficits. It is caused by the expansion of CGG repeats (55 to 200 repeats) in the noncoding region of the fragile X mental retardation 1 (FMR1) gene. Abnormal immunological patterns are often associated with neurodegenerative disorders and implicated in their etiology. We therefore investigated the immune status of FXTAS pa ...[more]

PMID: 23062006

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Project description:BackgroundIndividuals with premutation alleles of the fragile X mental retardation 1 (FMR1) gene are at risk of developing fragile X-associated tremor/ataxia syndrome (FXTAS) during aging. Characterization of motor issues associated with aging in FMR1 premutation carriers is needed to determine neurodegenerative processes and establish new biobehavioral indicators to help identify individuals at greatest risk of developing FXTAS.MethodsWe examined postural stability in 18 premutation carriers ages 46-77 years and 14 age-matched healthy controls. Participants completed a test of static stance and two tests of dynamic postural sway on a force platform to quantify postural variability and complexity. CGG repeat length was measured for each premutation carrier, and MRI and neurological evaluations were conducted to identify carriers who currently met criteria for FXTAS. Of the 18 premutation carriers, seven met criteria for definite/probable FXTAS (FXTAS+), seven showed no MRI or neurological signs of FXTAS (FXTAS-), and four were inconclusive due to insufficient data.ResultsCompared to controls, premutation carriers showed increased center of pressure (COP) variability in the mediolateral (COPML) direction during static stance and reduced COP variability in the anterior-posterior (COPAP) direction during dynamic AP sway. They also showed reductions in COPML complexity during each postural condition. FXTAS+ individuals showed reduced COPAP variability compared to FXTAS- carriers and healthy controls during dynamic AP sway. Across all carriers, increased sway variability during static stance and decreased sway variability in target directions during dynamic sways were associated with greater CGG repeat length and more severe neurologically rated posture and gait abnormalities.ConclusionOur findings indicate that aging FMR1 premutation carriers show static and dynamic postural control deficits relative to healthy controls implicating degenerative processes of spinocerebellar and cerebellar-brainstem circuits that may be independent of or precede the onset of FXTAS. Our finding that FXTAS+ and FXTAS- premutation carriers differed on their level of intentional AP sway suggests that neural mechanisms of dynamic postural control may be differentially impacted in patients with FXTAS, and its measurement may be useful for rapidly and precisely identifying disease presence and onset.

Project description:Fragile X premutation alleles have 55-200 CGG repeats in the 5' UTR of the FMR1 gene. Altered zinc (Zn) homeostasis has been reported in fibroblasts from >60 years old premutation carriers, in which Zn supplementation significantly restored Zn-dependent mitochondrial protein import/processing and function. Given that mitochondria play a critical role in synaptic transmission, brain function, and cognition, we tested FMRP protein expression, brain bioenergetics, and expression of the Zn-dependent synaptic scaffolding protein SH3 and multiple ankyrin repeat domains 3 (Shank3) in a knock-in (KI) premutation mouse model with 180 CGG repeats. Mitochondrial outcomes correlated with FMRP protein expression (but not FMR1 gene expression) in KI mice and human fibroblasts from carriers of the pre- and full-mutation. Significant deficits in brain bioenergetics, Zn levels, and Shank3 protein expression were observed in the Zn-rich regions KI hippocampus and cerebellum at PND21, with some of these effects lasting into adulthood (PND210). A strong genotype × age interaction was observed for most of the outcomes tested in hippocampus and cerebellum, whereas in cortex, age played a major role. Given that the most significant effects were observed at the end of the lactation period, we hypothesized that KI milk might have a role at compounding the deleterious effects on the FMR1 genetic background. A higher gene expression of ZnT4 and ZnT6, Zn transporters abundant in brain and lactating mammary glands, was observed in the latter tissue of KI dams. A cross-fostering experiment allowed improving cortex bioenergetics in KI pups nursing on WT milk. Conversely, WT pups nursing on KI milk showed deficits in hippocampus and cerebellum bioenergetics. A highly significant milk type × genotype interaction was observed for all three-brain regions, being cortex the most influenced. Finally, lower milk-Zn levels were recorded in milk from lactating women carrying the premutation as well as other Zn-related outcomes (Zn-dependent alkaline phosphatase activity and lactose biosynthesis-whose limiting step is the Zn-dependent ?-1,4-galactosyltransferase). In premutation carriers, altered Zn homeostasis, brain bioenergetics and Shank3 levels could be compounded by Zn-deficient milk, increasing the risk of developing emotional and neurological/cognitive problems and/or FXTAS later in life.

Dataset Information

Carriers of the fragile X mental retardation 1 (FMR1) premutation allele present with increased levels of cytokine IL-10.

Publications

Carriers of the fragile X mental retardation 1 (FMR1) premutation allele present with increased levels of cytokine IL-10.

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