24S-hydroxycholesterol suppresses neuromuscular transmission in SOD1(G93A) mice: A possible role of NO and lipid rafts

Cholesterol and the Safety Factor for Neuromuscular Transmission

“…This cholesterol could organize membrane microdomains, lipid rafts. Indeed, axonal synaptic membranes of frog, mouse and rat showed a high intensity of staining with lipid raft markers [35,37,38,39]. Moreover, acute cholesterol depletion with methyl-β-cyclodextrin (MβCD) led to decrease a lipid raft labeling [37,39].…”

“…Indeed, axonal synaptic membranes of frog, mouse and rat showed a high intensity of staining with lipid raft markers [35,37,38,39]. Moreover, acute cholesterol depletion with methyl-β-cyclodextrin (MβCD) led to decrease a lipid raft labeling [37,39]. All together, these results suggest that the membrane regions of AZ can have a relatively low cholesterol content, but other regions of the presynaptic membranes are cholesterol rich and contain lipid rafts, which could organize fence around AZ.…”

“…Cholesterol is oxidized by ROS and specific enzymes to oxysterols, which could modulate multiple processes, linked with inflammatory reactions and neurodegeneration [19,54,55]. Synaptic transmission in NMJs of frog and mouse was a high sensitive to different oxysterols and enzymatic cholesterol oxidation [37,38,39,56,57]. 24S-hydroxycholesterol (24HC) is a product of cholesterol metabolism, which is generated specifically in brain and passes across a blood–brain barrier into the circulation.…”

“…In an amyotrophic lateral sclerosis (ALS) mouse model carrying a mutant superoxide dismutase 1 (SOD1 G93A ) 24HC also decreased NO production, but led to an opposite effect on neuromuscular transmission, because the role of NO is likely reversed in ALS mice as compared to wild type mice. Increased NO synthesis promoted SV exocytosis during intense activity in SOD1 G93A mice, but it suppressed the exocytosis in wild type mice [39]. Probably, attenuation of NO production was mediated by increased lipid raft integrity in response to 24HC.…”

“…Probably, attenuation of NO production was mediated by increased lipid raft integrity in response to 24HC. Indeed, disturbance of lipid rafts prevented the effect of 24HC on NO synthesis [39]. However, it is unclear why NO had opposite actions in the ALS versus wild type mice.…”