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A metabolomic and systems biology perspective on the brain of the Fragile X syndrome mouse model
- Source :
- Genome Research, Genome Research, Cold Spring Harbor Laboratory Press, 2011, 21 (12), pp.2190-202. ⟨10.1101/gr.116764.110⟩, Genome Research, Cold Spring Harbor Laboratory Press, 2011, 21 (12), pp.2190-202. 〈10.1101/gr.116764.110〉, Genome research 21 (2011): 2190–2202. doi:10.1101/gr.116764.110, info:cnr-pdr/source/autori:Davidovic, Laetitia; Navratil, Vincent; Bonaccorso, Carmela M.; Catania, Maria Vincenza; Bardoni, Barbara; Dumas, Marc-Emmanuel/titolo:A metabolomic and systems biology perspective on the brain of the Fragile X syndrome mouse model/doi:10.1101%2Fgr.116764.110/rivista:Genome research/anno:2011/pagina_da:2190/pagina_a:2202/intervallo_pagine:2190–2202/volume:21
- Publication Year :
- 2011
- Publisher :
- COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT, 2011.
-
Abstract
- Fragile X syndrome (FXS) is the first cause of inherited intellectual disability, due to the silencing of the X-linked Fragile X Mental Retardation 1 gene encoding the RNA-binding protein FMRP. While extensive studies have focused on the cellular and molecular basis of FXS, neither human Fragile X patients nor the mouse model of FXS—the Fmr1-null mouse—have been profiled systematically at the metabolic and neurochemical level to provide a complementary perspective on the current, yet scattered, knowledge of FXS. Using proton high-resolution magic angle spinning nuclear magnetic resonance (1H HR-MAS NMR)-based metabolic profiling, we have identified a metabolic signature and biomarkers associated with FXS in various brain regions of Fmr1-deficient mice. Our study highlights for the first time that Fmr1 gene inactivation has profound, albeit coordinated consequences in brain metabolism leading to alterations in: (1) neurotransmitter levels, (2) osmoregulation, (3) energy metabolism, and (4) oxidative stress response. To functionally connect Fmr1-deficiency to its metabolic biomarkers, we derived a functional interaction network based on the existing knowledge (literature and databases) and show that the FXS metabolic response is initiated by distinct mRNA targets and proteins interacting with FMRP, and then relayed by numerous regulatory proteins. This novel “integrated metabolome and interactome mapping” (iMIM) approach advantageously unifies novel metabolic findings with previously unrelated knowledge and highlights the contribution of novel cellular pathways to the pathophysiology of FXS. These metabolomic and integrative systems biology strategies will contribute to the development of potential drug targets and novel therapeutic interventions, which will eventually benefit FXS patients.
- Subjects :
- Method
MESH : Brain Chemistry
Interactome
MESH: Mice, Knockout
Fragile X Mental Retardation Protein
Mice
0302 clinical medicine
Drug Delivery Systems
Intellectual disability
MESH: Animals
MESH: Brain Chemistry
Genetics (clinical)
Genetics
Mice, Knockout
0303 health sciences
Systems Biology
MESH : Metabolome
Brain
MESH : Fragile X Mental Retardation Protein
Fragile X syndrome
MESH : Fragile X Syndrome
MESH: Systems Biology
Metabolome
MESH : Drug Delivery Systems
MESH: Fragile X Syndrome
MESH: Metabolome
congenital, hereditary, and neonatal diseases and abnormalities
Systems biology
MESH: Drug Delivery Systems
Computational biology
[SDV.BC]Life Sciences [q-bio]/Cellular Biology
Biology
MESH: Fragile X Mental Retardation Protein
03 medical and health sciences
MESH: Brain
Metabolomics
Neurochemical
MESH : Mice
medicine
Gene silencing
Animals
Humans
[SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology
[ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology
MESH: Mice
030304 developmental biology
MESH : Systems Biology
Brain Chemistry
MESH: Humans
[ SDV.BC ] Life Sciences [q-bio]/Cellular Biology
MESH : Humans
MESH: Biological Markers
medicine.disease
MESH : Disease Models, Animal
MESH : Biological Markers
Disease Models, Animal
MESH : Brain
Fragile X Syndrome
MESH : Mice, Knockout
MESH : Animals
MESH: Disease Models, Animal
030217 neurology & neurosurgery
Biomarkers
Subjects
Details
- Language :
- English
- ISSN :
- 10889051 and 15495469
- Database :
- OpenAIRE
- Journal :
- Genome Research, Genome Research, Cold Spring Harbor Laboratory Press, 2011, 21 (12), pp.2190-202. ⟨10.1101/gr.116764.110⟩, Genome Research, Cold Spring Harbor Laboratory Press, 2011, 21 (12), pp.2190-202. 〈10.1101/gr.116764.110〉, Genome research 21 (2011): 2190–2202. doi:10.1101/gr.116764.110, info:cnr-pdr/source/autori:Davidovic, Laetitia; Navratil, Vincent; Bonaccorso, Carmela M.; Catania, Maria Vincenza; Bardoni, Barbara; Dumas, Marc-Emmanuel/titolo:A metabolomic and systems biology perspective on the brain of the Fragile X syndrome mouse model/doi:10.1101%2Fgr.116764.110/rivista:Genome research/anno:2011/pagina_da:2190/pagina_a:2202/intervallo_pagine:2190–2202/volume:21
- Accession number :
- edsair.doi.dedup.....00e5d5ecdac018891058b05de5ff1755