title: Neuronal cholesterol metabolism increases dendritic outgrowth and synaptic markers via a concerted action of GGTase-I and Trk.
abstract: Cholesterol 24-hydroxylase (CYP46A1) is responsible for brain cholesterol elimination and therefore plays a crucial role in the control of brain cholesterol homeostasis. Altered CYP46A1 expression has been associated with several neurodegenerative diseases and changes in cognition. Since CYP46A1 activates small guanosine triphosphate-binding proteins (sGTPases), we hypothesized that CYP46A1 might be affecting neuronal development and function by activating tropomyosin-related kinase (Trk) receptors and promoting geranylgeranyl transferase-I (GGTase-I) prenylation activity. Our results show that CYP46A1 triggers an increase in neuronal dendritic outgrowth and dendritic protrusion density, and elicits an increase of synaptic proteins in the crude synaptosomal fraction. Strikingly, all of these effects are abolished by pharmacological inhibition of GGTase-I activity. Furthermore, CYP46A1 increases Trk phosphorylation, its interaction with GGTase-I, and the activity of GGTase-I, which is crucial for the enhanced dendritic outgrowth. Cholesterol supplementation studies indicate that cholesterol reduction by CYP46A1 is the necessary trigger for these effects. These results were confirmed in vivo, with a significant increase of p-Trk, pre- and postsynaptic proteins, Rac1, and decreased cholesterol levels, in crude synaptosomal fractions prepared from CYP46A1 transgenic mouse cortex. This work describes the molecular mechanisms by which neuronal cholesterol metabolism effectively modulates neuronal outgrowth and synaptic markers.
authors: Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Portugal, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal.
authors: Miguel
authors: M
authors: Moutinho
authors: Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Portugal, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal.
authors: Maria João
authors: MJ
authors: Nunes
authors: Department of Physiology and Pharmacology, Molecular and Cellular Exercise Physiology, Karolinska Institutet, 17177 Stockholm, Sweden.
authors: Jorge C
authors: JC
authors: Correia
authors: Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Portugal, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal.|Department of Biochemistry and Human Biology, Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal.
authors: Maria João
authors: MJ
authors: Gama
authors: Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Portugal, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal.|Department of Life Sciences, Faculty of Science and Technology, Universidade NOVA de Lisboa, 2829-516 Caparica, Portugal.
authors: Margarida
authors: M
authors: Castro-Caldas
authors: Department of Neurobiology, Care Sciences and Society, Karolinska Institutet-Alzheimer's Disease Research Center, Novum, Stockholm, Sweden.
authors: Angel
authors: A
authors: Cedazo-Minguez
authors: Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Portugal, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal.|Department of Biochemistry and Human Biology, Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal.
authors: Cecília M P
authors: CM
authors: Rodrigues
authors: Department of Laboratory Medicine, Division of Clinical Chemistry, Karolinska Institutet, Karolinska University Hospital, Huddinge, Sweden.
authors: Ingemar
authors: I
authors: Björkhem
authors: Department of Physiology and Pharmacology, Molecular and Cellular Exercise Physiology, Karolinska Institutet, 17177 Stockholm, Sweden.
authors: Jorge L
authors: JL
authors: Ruas
authors: Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Portugal, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal.|Department of Biochemistry and Human Biology, Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal.
authors: Elsa
authors: E
authors: Rodrigues
mesh_terms: D019883:Alkyl and Aryl Transferases / Q000378:metabolism*; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism*; D000072556:Cholesterol 24-Hydroxylase / Q000235:genetics; D054351:Electrical Synapses; D005260:Female; D051379:Mice; D008822:Mice, Transgenic; D000071446:Neuronal Outgrowth; D009474:Neurons / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D020917:Receptor, trkA / Q000378:metabolism*
chemical_list: D015415:Biomarkers; D002784:Cholesterol; D000072556:Cholesterol 24-Hydroxylase; D019883:Alkyl and Aryl Transferases; C083291:geranylgeranyltransferase type-I; D020917:Receptor, trkA