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

ABSTRACT: 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.

SUBMITTER: Kaya I

PROVIDER: S-EPMC10372136 | biostudies-literature | 2023 Jul

REPOSITORIES: biostudies-literature

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

Kaya Ibrahim I Nilsson Anna A Luptáková Dominika D He Yachao Y Vallianatou Theodosia T Bjärterot Patrik P Svenningsson Per P Bezard Erwan E Andrén Per E PE

NPJ Parkinson's disease 20230726 1

Metabolism of MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) to the neurotoxin MPP<sup>+</sup> 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 nume ...[more]

PMID: 37495571

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Project description:Parkinson's disease (PD) is characterized by dopaminergic neurodegeneration in the nigrostriatal region of the brain; however, the neurodegeneration extends well beyond dopaminergic neurons. To gain a better understanding of the molecular changes relevant to PD, we applied two-dimensional LC-MS/MS to comparatively analyze the proteome changes in four brain regions (striatum, cerebellum, cortex, and the rest of brain) using a MPTP-induced PD mouse model with the objective to identify potential nigrostriatal-specific and other region-specific protein abundance changes. The combined analyses resulted in the identification of 4,895 nonredundant proteins with at least two unique peptides per protein. The relative abundance changes in each analyzed brain region were estimated based on the spectral count information. A total of 518 proteins were observed with substantial MPTP-induced abundance changes across different brain regions. A total of 270 of these proteins were observed with specific changes occurring either only in the striatum and/or in the rest of the brain region that contains substantia nigra, suggesting that these proteins are associated with the underlying nigrostriatal pathways. Many of the proteins that exhibit changes were associated with dopamine signaling, mitochondrial dysfunction, the ubiquitin system, calcium signaling, the oxidative stress response, and apoptosis. A set of proteins with either consistent change across all brain regions or with changes specific to the cortex and cerebellum regions were also detected. Ubiquitin specific protease (USP9X), a deubiquination enzyme involved in the protection of proteins from degradation and promotion of the TGF-beta pathway, exhibited altered abundance in all brain regions. Western blot validation showed similar spatial changes, suggesting that USP9X is potentially associated with neurodegeneration. Together, this study for the first time presents an overall picture of proteome changes underlying both nigrostriatal pathways and other brain regions potentially involved in MPTP-induced neurodegeneration. The observed molecular changes provide a valuable reference resource for future hypothesis-driven functional studies of PD.

Project description:Parkinson's disease (PD) is an age-associated neurodegenerative disorder hallmarked by a loss of mesencephalic dopaminergic neurons. Accurate recapitulation of the PD movement phenotype in animal models of the disease is critical for understanding disease etiology and developing novel therapeutic treatments. However, most existing behavioral assays currently applied to such animal models fail to adequately detect and subsequently quantify the subtle changes associated with the progressive stages of PD. In this study, we used a video-based analysis system to develop and validate a novel protocol for tracking locomotor performance in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. We anticipated that (1) treated mice should use slower, shorter, and less frequent strides and (2) that gait deficits should monotonically increase following MPTP administration, as the effects of neurodegeneration become manifest. Video-based biomechanical analyses, utilizing behavioral measures motivated by the comparative biomechanics literature, were used to quantify gait dynamics over a seven-day period following MPTP treatment. Analyses revealed shuffling behaviors consistent with the gait symptoms of advanced PD in humans. Here we also document dramatic gender-based differences in locomotor performance during the progression of the MPTP-induced lesion, despite male and female mice showing similar losses of striatal dopaminergic cells following MPTP administration. Whereas female mice appeared to be protected against gait deficits, males showed multiple changes in gait kinematics, consistent with the loss of locomotor agility and stability. Overall, these data show that the novel video analysis protocol presented here is a robust method capable of detecting subtle changes in gait biomechanics in a mouse model of PD. Our findings indicate that this method is a useful means by which to easily and economically screen preclinical therapeutic compounds for protecting against or reversing neuropathology associated with PD neurodegeneration.

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

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

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