Enzymatic Degradation of Brain Complex Gangliosides to Increase Endogenous GM1 Levels: Potential Neuroprotective/Neurorestorative Therapy for Parkinson’s disease

Objective/Rationale:
Pre-clinical studies and clinical studies with GM1 ganglioside in Parkinson’s disease patients suggest potential symptomatic and disease modifying effects of GM1 on Parkinson’s disease. However, an alternative therapeutic approach to administering exogenous GM1 might be to enhance endogenous levels of GM1 in the brain. One potential way to do this is by administering sialidases, enzymes that convert complex gangliosides to GM1 while reducing levels of potentially harmful gangliosides.

Project Description:
We will evaluate the effects of administration of two different sialidases on the ability to protect the nigrostriatal dopamine system in a pre-clinical model of Parkinsonism (using the neurotoxin MPTP) and compare this to the response produced by exogenously administered GM1.  Different doses of sialidases (or non-active vehicle) will be continuously infused directly into the brain for a 28 day period. Beginning with the second week of sialidase (or vehicle) administration, some animals will receive MPTP injections twice daily for 5 days.  At the end of the 28 day sialidase (or vehicle) administration period, brains will be analyzed to examine dopamine levels, numbers of dopamine neurons and changes in brain ganglioside levels. For comparison with GM1 treatment, additional groups of pre-clinical models will receive MPTP injections (twice daily for 5 days) followed by two weeks of GM1 administration.

Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Although symptomatic improvement can be obtained with currently available therapies, Parkinson’s disease is a progressive disorder and functional ability deteriorates over time.  Development of therapies that can slow progression of the disease would fill a major unmet medical need in Parkinson’s disease. If sialidase therapy is effective, it could be potentially administered to newly diagnosed Parkinson’s disease patients as well as to more advanced patients to slow the decline of functional ability and perhaps delay development of known treatment complications. 

Anticipated Outcome:
This research will allow us to examine the extent to which the administration of sialidase may be a potential therapy for Parkinsons’s disease.  We will learn whether pre-clinical models that receive MPTP and administration of sialidase have significantly higher dopamine levels and more dopamine neurons than pre-clinical models that receive MPTP and only a non-active vehicle. Results of these studies will tell us whether this therapy increases levels of GM1 and if effects of sialidases are similar to or better than the effects of administration of GM1 itself.