High Glucosylceramides and Low Anandamide Contribute to Sensory Loss and Pain in Parkinson's Disease

Abstract

A BS TRACT: Background: Parkinson's disease (PD) causes chronic pain in two-thirds of patients, in part originating from sensory neuropathies. The aim of the present study was to describe the phenotype of PDassociated sensory neuropathy and to evaluate its associations with lipid allostasis, the latter motivated by recent genetic studies associating mutations of glucocerebrosidase with PD onset and severity. Glucocerebrosidase catalyzes the metabolism of glucosylceramides. Methods: We used quantitative sensory tests, pain ratings, and questionnaires and analyzed plasma levels of multiple bioactive lipid species using targeted lipidomic analyses. The study comprised 2 sets of patients and healthy controls: the first 128 Israeli PD patients and 224 young German healthy controls for exploration, the second 50/50 German PD patients and matched healthy controls for deeper analyses. Results: The data showed a 70% prevalence of PD pain and sensory neuropathies with a predominant phenotype of thermal sensory loss plus mechanical hypersensitivity. Multivariate analyses of lipids revealed major differences between PD patients and healthy controls, mainly originating from glucosylceramides and endocannabinoids. Glucosylceramides were increased, whereas anandamide and lysophosphatidic acid 20:4 were reduced, stronger in patients with ongoing pain and with a linear relationship with pain intensity and sensory losses, particularly for glucosylceramide 18:1 and glucosylceramide 24:1. Conclusions: Our data suggest that PD-associated sensory neuropathies and PD pain are in part caused by accumulations of glucosylceramides, raising the intriguing possibility of reducing PD pain and sensory loss by glucocerebrosidase substituting or refolding approaches.

Sphingolipid and Endocannabinoid Profiles in Adult Attention Deficit Hyperactivity Disorder

“…The observed elevation of plasma S1P in our patients might imply that functional antagonists might be useful therapeutically for ADHD if the plasma levels indicated increased S1P signaling, which is presently unknown. In previous studies, S1P d18:1 plasma levels in patients with an affective disorder or neurologic diseases were not affected by the disease [ 29 , 39 , 69 ], but low S1Pd18:1 in association with high ceramides were observed in patients with dementia [ 70 ]. It has to be considered that the ages of dementia patients (avg.…”

“…Bioactive lipids, including sphingolipids and ceramides, and endocannabinoids, were analyzed in plasma by liquid chromatography-electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS) as described in recent previous publications [ 29 , 39 , 46 ].…”

“…Bioactive lipids, including sphingolipids and ceramides, and endocannabinoids, were analyzed in plasma by liquid chromatography-electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS) as described in recent previous publications [29,39,46]. Briefly, the determination of endocannabinoids, arachidonoyl ethanolamide (AEA), 2arachidonoyl glycerol (2-AG), 1-arachidonoyl glycerol (1-AG), oleoyl ethanolamide (OEA), and palmitoylethanolamide (PEA) was performed as described in detail in Reference [46].…”

“…Based on our previous studies in MD/BD patients [ 29 ] and patients with neuroinflammatory [ 38 ] and neurodegenerative diseases [ 39 ], we hypothesized that a set of sphingolipids and fatty acids would demark lipid profiles of adult ADHD patients and possibly predict comorbid outcomes. We, therefore, analyzed plasma concentrations of 23 lipid species (analytes and abbreviations in Supplementary Table S1 ) in ADHD patients, MD/BD patients, and patients with ADHD-MD/BD comorbidities versus healthy controls.…”

Failure of Diphtheria Toxin Model to Induce Parkinson-Like Behavior in Mice

“…SNCA spreading is also used to assess the prion-like spreading of glial SNCA inclusions to model the pathology of multiple system atrophy (MSA) [17], called MSA-prions [18]. MSA is a rapidly progressive synucleopathy arising from the misfolding and accumulation of SNCA species, mainly in oligodendrocytes [19], but transgenic models directing mutant SNCA to oligodendrocytes replicate only some aspects of human MSA [20,21], likely owing to complex genetics [22,23] and confounding lipid mediators such as glucosylceramides [24][25][26][27][28] and monounsaturated fatty acids [29][30][31] that can amplify the pathology of SNCA [32].…”