SCAP is required for timely and proper myelin membrane synthesis

Abstract

lipid metabolism ͉ neuron-glia interactions ͉ neuropathy ͉ X-ray diffraction T he rapid saltatory conduction of neuronal action potentials is crucially dependent on the insulating myelin membrane, an organelle synthesized by Schwann cells in the PNS, and by oligodendrocytes in the CNS (1). The electrical insulating property of the myelin membrane is provided by its high and characteristic lipid content with high levels of cholesterol, galactosphingolipids, and saturated long-chain fatty acids (1). Accordingly, metabolic disorders of cholesterol [e.g., Smith-Lemli-Opitz-syndrome and Tangier disease (2, 3)], galactosphingolipids (4, 5), or of fatty acid metabolism [Refsum's disease and diabetes mellitus (2)] often produce myelin defects.With the Schwann cell membrane surface area expanding a spectacular 6,500-fold during myelination (6), it is obvious that production of myelin membrane requires a large amount and diversity of myelin proteins and lipids. Myelination of peripheral nerves is a highly dynamic process with an acute phase that peaks in the second postnatal week in the mouse and a phase of steady-state maintenance in adult nerves (7). While it has been suggested that many of the myelin lipids are synthesized in the nerve itself, as was demonstrated for cholesterol (8, 9), the factors regulating their synthesis in myelinating Schwann cells are largely unknown. We recently profiled transcription in the peripheral nerve during myelination and found that sterol regulatory elementbinding proteins (SREBPs) are highly expressed in myelinating Schwann cells (10)(11)(12). SREBPs, consisting of SREBP-1a, SREBP1c, and SREBP-2, belong to the family of basic helix-loop-helixleucine zipper (bHLH-Zip) transcription factors that regulate lipid metabolism. SREBP-1c and SREBP-2 preferentially govern the transcriptional activation of genes involved in fatty acid and cholesterol metabolism, respectively, whereas SREBP-1a activates both pathways (13). SREBP transcription factors crucially rely on post-translational activation involving the sterol sensor SCAP. When sterol levels are low, SCAP escorts the SREBPs from the ER to the Golgi, where they are activated by processing through the membrane-associated proteases, S1P and S2P. The resulting mature and transcriptionally active forms of the SREBPs translocate to the nucleus where they bind genes containing sterol regulatory elements (13,14).Here, we determined the role of SCAP in myelination by its conditional ablation in Schwann cells. We found that deletion of SCAP seriously affected the dynamics of myelin membrane synthesis and caused neuropathy. However, these phenotypes improved with aging; SCAP mutant Schwann cells were able to slowly synthesize myelin, in an external lipid-dependent fashion, resulting in myelin membrane defects that are associated with abnormal lipid composition. Our data demonstrated the crucial role of SCAPmediated control of cholesterol and lipid metabolism necessary for production of a proper myelin membrane by Schwann cells.

Diabetes-induced myelin abnormalities are associated with an altered lipid pattern: protective effects of LXR activation

“…We also observed in the hyperglycemic state a reduction in myelin P0. It appears that diabetes modifi es myelin's lipid profi le and protein composition, changes that result in altered membrane fl uidity and myelin abnormalities ( 21,45 ). These data are consistent with work showing that changes in myelin lipid composition in STZ-treated animals correlate with altered biophysical properties of the myelin sheath, as assessed by electron spin resonance spectroscopy ( 22 ).…”

“…Diminished or abnormal FA synthesis may play an important role in altered myelin lipid and protein composition. Such changes in myelin could affect membrane fl uidity and function, ultimately contributing to the pathogenesis of DPN ( 21,22 ). In support of this notion, studies in animal models have revealed a protective effect of administration of FAs on DPN ( 23 ).…”

Disruption of astrocyte-neuron cholesterol cross talk affects neuronal function in Huntington’s disease

“…SREBP2 is expressed in glial cells and its activity likely controls the synthesis of lipids involved in various glia-neuron interactions, thereby affecting a range of neuronal functions. [43][44][45] SREBP1 and SREBP2 activities are reduced in the presence of mutant HTT, both in vitro and in vivo. 7 Although the details of the underlying molecular mechanism are unknown, mutant HTT likely interferes with the Golgi-tonucleus translocation of the active SREBP.…”

Myelination and mTOR

“…Third, no major contribution of exogenous palmitic, stearic, or oleic acid was detected in the developing brain (Edmond, Higa, Korsak, Bergner, & Lee, 1998; Marbois, Ajie, Korsak, Sensharma, & Edmond, 1992). Fourth, myelination was impaired after conditional deletion of enzymes necessary for cholesterol biosynthesis (squalene synthase) or deletion of SREBP‐cleavage activating protein (SCAP) upstream of SREBP transcription factors (see below) in myelinating cells (Saher et al, 2005, 2009; Verheijen et al, 2009). Thus, assuming a protein‐to‐lipid molar ratio in myelin of 1:186 (Gent, Gregson, Gammack, & Raper, 1964; O'Brien & Sampson, 1965), it appears likely that myelinating cells must synthesize several thousands of new lipid molecules per second.…”