ABSTRACT
The fact that Parkinson's disease (PD) pathologies are well advanced in most PD patients by the time of clinical elucidation attests to the importance of early diagnosis. Our attempt to achieve this has capitalized on our previous finding that GM1 ganglioside is expressed at subnormal levels in virtually all tissues of sporadic PD (sPD) patients including blood cells. GM1 is present in most vertebrate cells, is especially abundant in neurons where it was shown essential for their effective functioning and long term viability. We have utilized peripheral blood mononuclear cells (PBMCs) which, despite their low GM1, we found to be significantly lower in sPD patients compared to age-matched healthy controls. To quantify GM1 (and GD1a) we used high performance thin-layer chromatography combined with cholera toxin B linked to horseradish peroxidase, followed by densitometric quantification. GM1 was also deficient in PBMCs from PD patients with mutations in the glucocerebrosidase gene (PD-GBA), apparently even lower than in sPD. Reasons are given why we believe these results obtained with patients manifesting fully developed PD will apply as well to PD patients in preclinical stages-a topic for future study. We also suggest that these findings point to a potential disease altering therapy for PD once the early diagnosis is established.
Subject(s)
G(M1) Ganglioside/blood , G(M1) Ganglioside/deficiency , Parkinson Disease/blood , Parkinson Disease/diagnosis , Aged , Biomarkers/blood , Blood Chemical Analysis , Case-Control Studies , Early Diagnosis , Female , Gangliosides/blood , Glucosylceramidase/genetics , Humans , Leukocytes, Mononuclear/metabolism , Male , Middle Aged , Mutation , Parkinson Disease/genetics , ROC CurveABSTRACT
Parkinson's disease (PD) is a major neurodegenerative disorder characterized by a variety of non-motor symptoms in addition to the well-recognized motor dysfunctions that have commanded primary interest. We previously described a new PD mouse model based on heterozygous disruption of the B4galnt1 gene leading to partial deficiency of the GM1 family of gangliosides that manifested several nigrostriatal neuropathological features of PD as well as movement impairment. We now show this mouse also suffers three non-motor symptoms characteristic of PD involving the gastrointestinal, sympathetic cardiac, and cerebral cognitive systems. Treatment of these animals with a synthetic form of GM1 ganglioside, produced by transfected E. coli, proved ameliorative of these symptoms as well as the motor defect. These findings further suggest subnormal GM1 to be a systemic defect constituting a major risk factor in sporadic PD and indicate the B4galnt1(+/-) (HT) mouse to be a true neuropathological model that recapitulates both motor and non-motor lesions of this condition.
Subject(s)
Disease Models, Animal , G(M1) Ganglioside/administration & dosage , G(M1) Ganglioside/deficiency , N-Acetylgalactosaminyltransferases/deficiency , Parkinson Disease/drug therapy , Parkinson Disease/metabolism , Animals , Female , G(M1) Ganglioside/genetics , Gastrointestinal Diseases/drug therapy , Gastrointestinal Diseases/genetics , Gastrointestinal Diseases/metabolism , Male , Memory Disorders/drug therapy , Memory Disorders/genetics , Memory Disorders/metabolism , Mice , Mice, Inbred C57BL , Mice, Knockout , Mice, Transgenic , Motor Skills Disorders/drug therapy , Motor Skills Disorders/genetics , Motor Skills Disorders/metabolism , N-Acetylgalactosaminyltransferases/genetics , Parkinson Disease/geneticsABSTRACT
Given the recent in vitro discovery that the free soluble oligosaccharide of GM1 is the bioactive portion of GM1 for neurotrophic functions, we investigated its therapeutic potential in the B4galnt1+/- mice, a model of sporadic Parkinson's disease. We found that the GM1 oligosaccharide, systemically administered, reaches the brain and completely rescues the physical symptoms, reduces the abnormal nigral α-synuclein content, restores nigral tyrosine hydroxylase expression and striatal neurotransmitter levels, overlapping the wild-type condition. Thus, this study supports the idea that the Parkinson's phenotype expressed by the B4galnt1+/- mice is due to a reduced level of neuronal ganglioside content and lack of interactions between the oligosaccharide portion of GM1 with specific membrane proteins. It also points to the therapeutic potential of the GM1 oligosaccharide for treatment of sporadic Parkinson's disease.
