Brain-region-specific lipid dysregulation in L-DOPA-induced dyskinesia in a primate model of Parkinson’s disease

Kaya I, Vallianatou T, Nilsson A, Bjäterot P, Shariatgorji R, Svenningsson P, Bezard E, and Andren PE. (2025) Brain-region-specific lipid dysregulation in L-DOPA-induced dyskinesia in a primate model of Parkinson’s disease. Parkinson’s Disease

Parkinson’s disease (PD) is a progressive neurodegenerative disease that results from degeneration within the dopaminergic nigrostriatal pathway. This degeneration disrupts the function of the basal ganglia and causes a reduction in dopamine levels. PD is a movement disorder and those with it may experience tremors, rigid muscles, poor balance, loss of automatic movements, speech changes, as well as some nonmotor symptoms including depression, anxiety, and sleep problems. Levodopa (L-DOPA) treatment is very effective at reversing the motor symptoms in the early stages of PD, but prolonged use can cause involuntary movements which are coined L-DOPA-induced dyskinesia (LID). Since this treatment is so beneficial earlier in PD progression, there is interest in determining the mechanisms behind the development of LID and to discover other treatments that could prevent this from occurring. A growing area of interest in PD is the role of lipids since there are many strong links between PD and lipid alterations. Lipids are important for cellular functions such as cellular signaling, inflammation, cell growth and polarity, homeostasis, maintenance, and cell senescence. In addition, lipidomic studies have shown differences between post-mortem PD patient brains compared to healthy controls, however there are very few reports on LID-specific changes. In particular, Kaya et al were interested in determining the distribution of various glycerophospholipids in brain tissue sections from female non-human primate brains using high mass resolution MALDI-Fourier-transform ion cyclotron resonance (FTICR)-MSI and whether there were any brain region-specific alterations associated with LID.

The groups that Kaya et al analysed were control animals, animals with Parkinsonism induced by 1-methyl,4-phenyl-1,2,3,6 tetrahydropyridine (MPTP) administration, MPTP-treated animals that received chronic L-DOPA treatment without dyskinesia (non-LID group), and MPTP-treated animals that received chronic L-DOPA treatment exhibiting LID (LID group). They looked at motor regions including caudate, putamen, precentral gyrus, and internal and external segments of globus pallidus. Other areas analyzed were post central gyrus, temporal gyrus, insula, claustrum, anterior cingulate gyrus, temporal white matter, and cerebral white matter. The non-LID group and the LID groups were analyzed to identify which categories of lipids were altered between the groups and they found changes in plasmalogen phosphatidylcholines (PC-P), polyunsaturated fatty acid (PUFA)-containing glycerophospholipids, hydroxylated sphingolipids, and non-hydroxylated sphingolipids. When looking specifically at changes in plasmalogen PCs, a significant difference between the non-LID group and the LID group was found. The internal globus pallidus, claustrum, postcentral gyrus, and precentral gyrus demonstrated significant changes in plasmalogen PC levels. Significantly decreased levels in three plasmalogen PC species (PC-P(34:0), PC-P(36:0) and PC-P(36:1)) were seen in LID animals compared to non-LID animals within the internal globus pallidus, claustrum, and precentral gyrus. This trend was also seen in other brain regions including external globus pallidus, putamen, and precentral gyrus.

To assess the relationship between plasmalogen PCs and dyskinesia, the authors looked at the correlations between amount of plasmalogen PCs in brain regions and the animals’ dyskinesia behavioural scores, in addition to the L-DOPA and dopamine levels in those regions. Correlations were found between PC-P(34:0) and PC-P(36:0) and the LID scores in the internal globus pallidus, claustrum, and precentral gyrus. In addition, a correlation was found between PC-P(34:0), PC-P(36:0), and PC-P(36:1) and L-DOPA levels in the internal globus pallidus and the claustrum. Dopamine levels were also correlated to PC-P(34:0), PC-P(36:0), and PC-P(36:1) in the internal globus pallidus, claustrum, and precentral gyrus. The negative correlation seen between plasmalogen PC levels and the LID severity scores and L-DOPA and dopamine in these brain regions may indicate that plasmalogen PC reduction is associated with an increased susceptibility to LID.

Kaya et al were interested in evaluating the link between brain-region specific lipid alterations and L-DOPA-induced dyskinesia using the MPTP model of PD. Significant lipidomic dysregulation was detected in multiple lipid classes, but here we focused on those in plasmalogen PCs. Previously, differences in post-mortem PD brains and overall lipid alterations in plasma and cerebrospinal fluid have been demonstrated in patients with LID, however specific lipid species differences were not identified. The authors found distinct correlations between the changes in lipid species and clinical assessments including LID severity scores and levels of L-DOPA and dopamine. They demonstrated that a decrease in plasmalogen PCs was correlated with LID severity, L-DOPA levels, and dopamine levels in multiple brain regions, which suggests that a reduction in plasmalogen PCs could be linked to a susceptibility to LID. Plasmalogen PCs are important in membrane fluidity, and protecting from oxidative stress and a reduction in these lipids could explain some of the risk for LID. This work increases our knowledge of the mechanisms behind LID and supports the theory that treatments that target lipid metabolism could be an important method used to respond to LID.