Development of glycosphingolipid-reducing compounds as disease-modifying treatments for Parkinson’s disease

Parkinson’s Disease (PD) is caused by a degeneration of circumscribed regions of the brain including the dopaminergic neurons in the substantia nigra of the midbrain. Pathologically, PD is characterized by the accumulation of a-synuclein (a-syn) protein into oligomers and amyloid fibrils that comprise Lewy body inclusions. In addition to the sound documentation of Lewy inclusions in PD brain, several aggregationinducing genetic mutations in the a-syn gene have been identified in rare familial forms of PD. This suggests that a-syn causes neurotoxicity through a gain-in-toxic-function mechanism, and that reducing a-syn levels will provide benefit in PD and related synucleinopathies. This hypothesis is best supported by the observation that familial forms of PD are caused by duplication and triplication of the a-syn gene (SNCA), where triplication patients develop disease much earlier compared to duplication patients. This implies that dosage of a-syn is a critical pathogenic factor that mediates disease progression. Symptomatic treatments exist for PD, such as L-DOPA therapy, that can temporarily ameliorate the motor phenotype. However, there are currently no therapies that slow or hault the progression of dopaminergic cell death or prevent the accumulation of a-syn. Our approach to developing novel disease-modifying therapies for PD is centered around clearance of a-syn, by making it more susceptible to degradation by the lysosomal system.