title: SCAP is required for timely and proper myelin membrane synthesis.
abstract: Myelination requires a massive increase in glial cell membrane synthesis. Here, we demonstrate that the acute phase of myelin lipid synthesis is regulated by sterol regulatory element-binding protein (SREBP) cleavage activation protein (SCAP), an activator of SREBPs. Deletion of SCAP in Schwann cells led to a loss of SREBP-mediated gene expression involving cholesterol and fatty acid synthesis. Schwann cell SCAP mutant mice show congenital hypomyelination and abnormal gait. Interestingly, aging SCAP mutant mice showed partial regain of function; they exhibited improved gait and produced small amounts of myelin indicating a slow SCAP-independent uptake of external lipids. Accordingly, extracellular lipoproteins partially rescued myelination by SCAP mutant Schwann cells. However, SCAP mutant myelin never reached normal thickness and had biophysical abnormalities concordant with abnormal lipid composition. These data demonstrate that SCAP-mediated regulation of glial lipogenesis is key to the proper synthesis of myelin membrane, and provide insight into abnormal Schwann cell function under conditions affecting lipid metabolism.
authors: Department of Molecular and Cellular Neurobiology, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, VU University, 1081 HV Amsterdam, The Netherlands. mark.verheijen@cncr.vu.nl
authors: Mark H G
authors: MH
authors: Verheijen
authors: Nutabi
authors: N
authors: Camargo
authors: Valerie
authors: V
authors: Verdier
authors: Karim
authors: K
authors: Nadra
authors: Anne-Sophie
authors: AS
authors: de Preux Charles
authors: Jean-Jacques
authors: JJ
authors: Médard
authors: Adrienne
authors: A
authors: Luoma
authors: Michelle
authors: M
authors: Crowther
authors: Hideyo
authors: H
authors: Inouye
authors: Hitoshi
authors: H
authors: Shimano
authors: Su
authors: S
authors: Chen
authors: Jos F
authors: JF
authors: Brouwers
authors: J Bernd
authors: JB
authors: Helms
authors: M Laura
authors: ML
authors: Feltri
authors: Lawrence
authors: L
authors: Wrabetz
authors: Daniel
authors: D
authors: Kirschner
authors: Roman
authors: R
authors: Chrast
authors: August B
authors: AB
authors: Smit
mesh_terms: D000375:Aging; D000818:Animals; D005727:Ganglia, Spinal / Q000166:cytology; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology*; D050356:Lipid Metabolism; D008055:Lipids / Q000096:biosynthesis*; D050155:Lipogenesis; D008565:Membrane Proteins / Q000502:physiology*; D051379:Mice; D008817:Mice, Mutant Strains; D009154:Mutation; D009186:Myelin Sheath / Q000737:chemistry / Q000378:metabolism*; D009457:Neuroglia / Q000378:metabolism; D020127:Recovery of Function; D012583:Schwann Cells / Q000378:metabolism / Q000648:ultrastructure; D051779:Sterol Regulatory Element Binding Proteins / Q000502:physiology*
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D008055:Lipids; D008565:Membrane Proteins; C102196:SREBP cleavage-activating protein; D051779:Sterol Regulatory Element Binding Proteins