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Transcriptome-wide association study reveals cholesterol metabolism gene Lpl is a key regulator of cognitive dysfunction
- Source :
- Frontiers in Molecular Neuroscience, Vol 15 (2022)
- Publication Year :
- 2022
- Publisher :
- Frontiers Media S.A., 2022.
-
Abstract
- Cholesterol metabolism in the brain plays a crucial role in normal physiological function, and its aberrations are associated with cognitive dysfunction. The present study aimed to determine which cholesterol-related genes play a vital role in cognitive dysfunction and to dissect its underlying molecular mechanisms using a systems genetics approach in the BXD mice family. We first systematically analyzed the association of expression of 280 hippocampal genes related to cholesterol metabolism with cognition-related traits and identified lipoprotein lipase (Lpl) as a critical regulator. This was further confirmed by phenome-wide association studies that indicate Lpl associated with hippocampus volume residuals and anxiety-related traits. By performing expression quantitative trait locus mapping, we demonstrate that Lpl is strongly cis-regulated in the BXD hippocampus. We also identified ∼3,300 genes significantly (p < 0.05) correlated with the Lpl expression. Those genes are mainly involved in the regulation of neuron-related traits through the MAPK signaling pathway, axon guidance, synaptic vesicle cycle, and NF-kappa B signaling pathway. Furthermore, a protein–protein interaction network analysis identified several direct interactors of Lpl, including Rab3a, Akt1, Igf1, Crp, and Lrp1, which indicates that Lpl involves in the regulation of cognitive dysfunction through Rab3a-mediated synaptic vesicle cycle and Akt1/Igf1/Crp/Lrp1-mediated MAPK signaling pathway. Our findings demonstrate the importance of the Lpl, among the cholesterol-related genes, in regulating cognitive dysfunction and highlighting the potential signaling pathways, which may serve as novel therapeutic targets for the treatment of cognitive dysfunction.
Details
- Language :
- English
- ISSN :
- 16625099
- Volume :
- 15
- Database :
- Directory of Open Access Journals
- Journal :
- Frontiers in Molecular Neuroscience
- Publication Type :
- Academic Journal
- Accession number :
- edsdoj.909be154824840328e6d73027d82cf38
- Document Type :
- article
- Full Text :
- https://doi.org/10.3389/fnmol.2022.1044022