Neutral sphingomyelinase increases and delocalizes in the absence of Toll-Like Receptor 4: a new insight for MPTP Neurotoxicity

Both sphingomyelinase and Toll-Like Receptor 4 (TLR4) are implicated in neurodegenerative diseases. However, the relationship between the two molecules remains unclear. In this study, using WT and TLR4-deficient mice, treated or not with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), we aimed to investigate the relation between TLR4 and neutral sphingomyelinase (nSMase) in the midbrain. We found that the lack of TLR4 caused increase in nSMase protein expression and enzyme activity in the midbrain, as well as a marked delocalization from the cell membranes. This provoked a decrease in sphingomyelin (SM) species and an increase in ceramide levels. We found that exposure of TLR4-deficient mice to MPTP reduces unsaturated SM species by increasing saturated/unsaturated SM ratio. Saturated fatty acid make SM more rigid and could contribute to reducing neural plasticity. In this study we showed that the absence of TLR4 also induced reduction of both heavy neurofilaments and glial fibrillary acidic protein (GFAP) and and mice exhibited higher sensitivity to MPTP administration. We speculated about the possible association between nSMase-TLR4 complex and MPTP midbrain damage. Taken together, our findings provide for the first time indications about the role of TLR4 in change of SM metabolism in MPTP neurotoxicity.