Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 106, Issue 50, Pages 21383-21388Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0905633106
Keywords
lipid metabolism; neuron-glia interactions; neuropathy; X-ray diffraction
Categories
Funding
- Dutch Brain Foundation [13F05.50]
- European Union [EU-NEST 12702]
- Centre for Medical Systems Biology
- Marie Curie Foundation Host Fellowship [EST-2005 020919]
- Swiss National Science Foundation [PP00A-106714]
- National Institutes of Health [R01 NS045630, R01 NS055256]
- Telethon Italia [GGP08021, GGP071100]
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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.
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