RIT1 regulation of CNS lipids RIT1 deficiency Alters cerebral lipid metabolism and reduces white matter tract oligodendrocytes and conduction velocities

Lei Wu; Fang Wang; Carole L Moncman; Mritunjay Pandey; Harrison A Clarke; Hilaree N Frazier; Lyndsay E A Young; Matthew S Gentry; Weikang Cai; Olivier Thibault; Ramon C Sun; Douglas A Andres

doi:10.1016/j.heliyon.2023.e20384

RIT1 regulation of CNS lipids RIT1 deficiency Alters cerebral lipid metabolism and reduces white matter tract oligodendrocytes and conduction velocities

Heliyon. 2023 Sep 23;9(10):e20384. doi: 10.1016/j.heliyon.2023.e20384. eCollection 2023 Oct.

Authors

Lei Wu¹, Fang Wang¹, Carole L Moncman¹, Mritunjay Pandey¹, Harrison A Clarke², Hilaree N Frazier³, Lyndsay E A Young^{1

4}, Matthew S Gentry^{1

4

5

6}, Weikang Cai⁷, Olivier Thibault³, Ramon C Sun^{2

4

8

5

6}, Douglas A Andres^{1

4

9

10}

Affiliations

¹ Department of Molecular and Cellular Biochemistry, College of Medicine, University of Kentucky, KY 40536, USA.
² Department of Neuroscience, College of Medicine, University of Kentucky, KY 40536, USA.
³ Department of Pharmacological and Nutritional Sciences, College of Medicine, University of Kentucky, KY 40536, USA.
⁴ Markey Cancer Center, Lexington, KY 40536, USA.
⁵ Department of Biochemistry and Molecular Biology, University of Florida, College of Medicine, Gainesville, FL 32611, USA.
⁶ Center for Advanced Spatial Biomolecule Research, University of Florida, College of Medicine, Gainesville, FL 32611, USA.
⁷ Department of Biomedical Sciences, New York Institute of Technology College of Osteopathic Medicine, NY 11568, USA.
⁸ Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY 40536, USA.
⁹ Spinal Cord and Brain Injury Research Center, College of Medicine, University of Kentucky, KY 40536, USA.
¹⁰ Gill Heart and Vascular Institute, College of Medicine, University of Kentucky, Lexington, KY 40536, USA.

Abstract

Oligodendrocytes (OLs) generate lipid-rich myelin membranes that wrap axons to enable efficient transmission of electrical impulses. Using a RIT1 knockout mouse model and in situ high-resolution matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) coupled with MS-based lipidomic analysis to determine the contribution of RIT1 to lipid homeostasis. Here, we report that RIT1 loss is associated with altered lipid levels in the central nervous system (CNS), including myelin-associated lipids within the corpus callosum (CC). Perturbed lipid metabolism was correlated with reduced numbers of OLs, but increased numbers of GFAP⁺ glia, in the CC, but not in grey matter. This was accompanied by reduced myelin protein expression and axonal conduction deficits. Behavioral analyses revealed significant changes in voluntary locomotor activity and anxiety-like behavior in RIT1^KO mice. Together, these data reveal an unexpected role for RIT1 in the regulation of cerebral lipid metabolism, which coincide with altered white matter tract oligodendrocyte levels, reduced axonal conduction velocity, and behavioral abnormalities in the CNS.

Keywords: Endothelin-1; Lipidomics; MALDI-MSI; Myelin; Myelination; Oligodendrocyte progenitor cell; Ras; Rit GTPase.

Abstract

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