Characterization of brain cholesterol and its link with the neurophysiological profile in Fragile X Syndrome
Year: 2021
Type: dissertation
Study design: Observational Study
Abstract: Fragile X syndrome (FXS) is the most common single-gene cause of autism spectrum disorder (ASD). FXS is caused by mutations in the fragile mental retardation 1 (FMR1) gene, resulting in a deficiency or absence of Fragile-X-Mental Retardation Protein (FMRP). FMRP deficiency results in increased dendritic protein synthesis. Indeed, FXS is characterized by an alteration of the dendritic morphology and synaptic dysfunction. The latter leads to an imbalance between cortical excitation (glutamatergic) and inhibition (GABAergic). Specifically, cortical hyperexcitability was found in FXS individuals, using transcranial magnetic stimulation (TMS). In addition, our preliminary results suggest a decrease in 24-hydroxycholesterol (24-OHC) and 27-hydroxycholesterol (27-OHC), the major metabolites of the brain and peripheral cholesterol respectively. Disturbance of brain cholesterol homeostasis has been described in several cognitive disorders. Considering the essential role of brain cholesterol in signaling and synaptogenesis, it is important to explore how brain cholesterol abnormalities translate into neurophysiological profile in FXS. The primary objectives of this study thesis are: (1) to Quantify 24-OHC and 27-OHC levels in FXS individuals; (2) to assess cortical excitability in FXS individuals; (4) to investigate the association between 24-OHC, 27-OHC, and cortical excitability. Materials and methods: In order to meet our objectives, 12 FXS individuals were recruited via the CHUS Fragile X Clinic. A blood sample was collected followed by a TMS session. On the blood sample, 24-OHC and 27-OHC were quantified by LC-MS/MS. The TMS parameters studied were intra-cortical inhibition (SICI) and intra-cortical facilitation (LICI) in the long and short term. Spearman correlations were used to study the associations between oxysterols and TMS parameters. Results: A positive and significant correlation was obtained between 24-OHC (rs = 0,83; p = 0,008), the 24-OHC/27-OHC ratio (rs= 0,65; p = 0,049), and LICI in FXS individuals. Conclusion: Our results suggest an alteration of cerebral cholesterol in FXS individuals that could be related to the observed hyperexcitability.
Author: Laroui, Asma
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: green
Award: G6910506812
OpenAlex ID: W7201930383