Journal
JOURNAL OF PROTEOMICS
Volume 269, Issue -, Pages -Publisher
ELSEVIER
DOI: 10.1016/j.jprot.2022.104720
Keywords
FMRP; Lysine acetylome; Energy metabolism; Hippocampus
Categories
Funding
- Basic and Applied Basic Research Foundation of Guangdong Province [2021A1515220014]
- National Natural Science Foundation of China [81671112]
Ask authors/readers for more resources
This study identified a global hippocampal lysine acetylome and an altered K-ac protein profile upon loss of FMRP. The altered K-ac proteins were enriched in energy metabolic processes and implicated in several neurological disorders. The deficiency of FMRP also induced changes in key enzymes, ATP levels, and lactate in the mouse hippocampus and hippocampal cells.
Loss of fragile X retardation protein (FMRP) leads to fragile X syndrome (FXS), a common cause of inherited intellectual disability. Protein lysine acetylation (K-ac), a reversible post-translational modification of proteins, is associated with the regulation of brain development and neuropathies. However, a comprehensive hippocampal K-ac protein profile in response to FMRP deficiency has not been reported until now. Using LC-MS/MS to analyze the enriched K-ac peptides, this study identified 1629 K-ac hits across 717 proteins in the mouse hippocampus, and these proteins were enriched in several metabolic processes. Of them, 51 K-ac hits across 45 proteins were significantly changed upon loss of FMRP. These altered K-ac proteins were enriched in energy metabolic pro-cesses including carboxylic acid metabolism process, aerobic respiration and citrate cycle, linking with several neurological disorders such as lactic acidosis, Lewy body disease, Leigh disease and encephalopathies. In the mouse hippocampus and the hippocampal HT-22 cells, FMRP deficiency could induce altered K-ac modification of several key enzymes, decrease in ATP and increase in lactate. Thus, this study identified a global hippocampal lysine acetylome and an altered K-ac protein profile upon loss of FMRP linked to abnormal energy metabolism, implicating in the pathogenesis of FXS.Significance: Fragile X syndrome (FXS) is a common inherited neurodevelopment disorder characterized by in-tellectual disability and an increased risk for autism spectrum disorder. FXS is resulted from silencing of the FMR1 gene, which induces loss of its encoding protein FMRP. Molecular and metabolic changes of Fmr1-null animal models of FXS have been identified to potentially contribute to the pathogenesis of FXS. Here, we used a TMT-labeled quantitative proteomic analysis of the peptides enriched by anti-K-ac antibodies and identified a global K-ac protein profile in the mouse hippocampus with a total of 1629 K-ac peptides on 717 proteins. Of them, 51 K-ac peptides regarding 45 proteins altered in response to loss of FMRP, which were enriched in energy metabolic processes and were implicated in several neurological disorders. Thus this study for the first time provides a global hippocampal lysine acetylome upon FMRP deficiency linked to abnormal metabolic pathways, which may contribute to pathogenic mechanism of FXS.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available