Cholesterol Depletion Sensitivity in a Slow Channel Congenital Myasthenic Syndrome Mouse Model: Cav‐1's Role on the Neuromuscular Junction

Abstract

Cholesterol is known to modulate membrane's biophysical properties plus influence in the function and trafficking of membrane proteins. We have shown that point mutations in the nicotinic acetylcholine receptor (nAChR) can evoke increased macroscopic responses upon cholesterol depletion and at the same time, some can result in a Slow Channel Congenital Myasthenic Syndrome (SCCMS) characterized by muscle weakness and fatigue. Our main goal is to characterize a cholesterol reduction treatment in a model in which both the SCCMS and the cholesterol sensitivity phenotype coexist, αC418W mutation. Using various approaches, we uncovered a fraction of αC418W located in caveolin‐1 rich domains, suggesting a non‐functional state and possibly susceptible to cholesterol levels. Cholesterol depletion by Lipitor® resulted in the rearrangement of these receptors to a now functional pool. After treatment, the model presented calcium overload, high caspase activity, lower motor activity and significant differentiation in relation to the neuromuscular junction and its volume under confocal microscopy. Better molecular understanding of the statins' role on membrane proteins and cholesterol's participation is crucial for novel approaches to old physiological phenomena's that haven't been solved. Ultimately addressing the biggest problem, are statins safe?