Spatial lipidomics reveals brain region-specific changes of sulfatides in an experimental MPTP Parkinson's disease primate model

Metabolism of MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) to the neurotoxin MPP+ in the brain causes permanent Parkinson's disease-like symptoms by destroying dopaminergic neurons in the pars compacta of the substantia nigra in humans and non-human primates. However, the complete molecular pathology underlying MPTP-induced parkinsonism remains poorly understood. We used dual polarity matrix-assisted laser desorption/ionization mass spectrometry imaging to thoroughly image numerous glycerophospholipids and sphingolipids in coronal brain tissue sections of MPTP-lesioned and control non-human primate brains (Macaca mulatta). The results revealed specific distributions of several sulfatide lipid molecules based on chain-length, number of double bonds, and importantly, hydroxylation stage. More specifically, certain long-chain hydroxylated sulfatides with polyunsaturated chains in the molecular structure were depleted within motor-related brain regions in the MPTP-lesioned animals, e.g., external and internal segments of globus pallidus and substantia nigra pars reticulata. In contrast, certain long-chain non-hydroxylated sulfatides were found to be elevated within the same brain regions. These findings demonstrate region-specific dysregulation of sulfatide metabolism within the MPTP-lesioned macaque brain. The depletion of long-chain hydroxylated sulfatides in the MPTP-induced pathology indicates oxidative stress and oligodendrocyte/myelin damage within the pathologically relevant brain regions. Hence, the presented findings improve our current understanding of the molecular pathology of MPTP-induced parkinsonism within primate brains, and provide a basis for further research regarding the role of dysregulated sulfatide metabolism in PD.

Automated summary

Metabolism of MPTP leads to the neurotoxin MPP+, which causes Parkinson's disease-like symptoms by destroying dopaminergic neurons in the brain. This study used mass spectrometry imaging to analyze glycerophospholipids and sphingolipids in monkey brains and found dysregulation of sulfatide metabolism in the MPTP-lesioned brain regions. Depletion of long-chain hydroxylated sulfatides suggests oxidative stress and damage to myelin in these regions. These findings contribute to our understanding of the molecular pathology of MPTP-induced parkinsonism and provide a basis for further research on dysregulated sulfatide metabolism in Parkinson's disease.