Parkinson’s disease (PD) is a neurodegenerative movement disorder involving the selective loss of dopamine-producing neurons in the substantia nigra (SN). Differences in disease presentation, prevalence, and age of onset have been reported between males and females with PD. The content and composition of the major glycosphingolipids, phospholipids, and cholesterol were evaluated in the SN from 12 PD subjects and in 18 age-matched, neurologically normal controls. Total SN ganglioside sialic acid content and water content (%) were significantly lower in the male PD subjects than in the male controls. The content of all major gangliosides were reduced in the male PD subjects to some degree, but the neuronal-enriched gangliosides, GD1a and GT1b, were most significantly reduced. The distribution of phosphatidylethanolamine, phosphatidylcholine, and phosphatidylinositol was also significantly lower in the male PD subjects than in the male controls. However, the distribution of myelin-enriched cerebrosides and sulfatides was significantly higher in the male PD subjects than in the male controls suggesting myelin sparing in the male PD subjects. No elevation was detected for astrocytosis-linked GD3. These neurochemical changes provide evidence of selective neuronal loss in SN of the males with PD without robust astrocytosis. In contrast to the SN lipid abnormalities found in the male PD subjects, no significant abnormalities were found in the female PD subjects for SN water content or for any major SN lipids. These data indicate sex-related differences in SN lipid abnormalities in PD.

BackgroundPreclinical and clinical studies have previously shown that systemic administration of GM1 ganglioside has neuroprotective and neurorestorative properties in Parkinson’s disease (PD) models and in PD patients. However, the clinical development of GM1 for PD has been hampered by its animal origin (GM1 used in previous studies was extracted from bovine brains), limited bioavailability, and limited blood brain barrier penetrance following systemic administration.ObjectiveTo assess an alternative therapeutic approach to systemic administration of brain-derived GM1 to enhance GM1 levels in the brain via enzymatic conversion of polysialogangliosides into GM1 and to assess the neuroprotective potential of this approach.MethodsWe used sialidase from Vibrio cholerae (VCS) to convert GD1a, GD1b and GT1b gangliosides to GM1. VCS was infused by osmotic minipump into the dorsal third ventricle in mice over a 4-week period. After the first week of infusion, animals received MPTP injections (20 mg/kg, s.c., twice daily, 4 hours apart, for 5 consecutive days) and were euthanized 2 weeks after the last injection.ResultsVCS infusion resulted in the expected change in ganglioside expression with a significant increase in GM1 levels. VCS-treated animals showed significant sparing of striatal dopamine (DA) levels and substantia nigra DA neurons following MPTP administration, with the extent of sparing of DA neurons similar to that achieved with systemic GM1 administration.ConclusionThe results suggest that enzymatic conversion of polysialogangliosides to GM1 may be a viable treatment strategy for increasing GM1 levels in the brain and exerting a neuroprotective effect on the damaged nigrostriatal DA system.