L-PDMP, Ganglioside Synthesis Enhancer Protects Dopaminergic Neurons from Death by Proteasomal Inhibition and the Accumulation of alpha-synuclein / 체질인류학회지

ABSTRACT

Gangliosides are components of the membranous constituents and abundant in the nervous system. And they are implicated in a wide range of biological activities including the regulation of cell proliferation, differentiation and lysosomal activity. But they have a diverse action to induce neuronal cell death by the interaction with some ligands. The interference of their biosynthesis is accompanied by the intracellular accumulation of unwanted and neurotoxic proteins and might underlie the neurodegeneration diseases including Parkinson's disease. However the mechanism has not been elucidated. In this study, we report that the enhancement of biosynthesis of ganglioside GD3 protects the intracellular accumulation of alpha-synuclein and neuronal death. PC12 cells, dopaminergic neurons are cultured with synthetic proteasomal inhibitor (PSI, Z-lle-Glu(OtBu)-Ala-Leu-al) and L-PDMP (GD3 synthetase enhancer, L-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol). We found that the neuronal viability was recovered by L-PDMP from the proteasomal inhibition and also the expression of activated caspase-3 and PARP was reduced. L-PDMP decreased in the intracellular accumulation of alpha-synuclein. Interestingly, PSI induced the expression of ganglioside3 in PC12 cell. Our findings suggest that proteasomal inhibition may modulate the biosynthesis of GD3 and L-PDMP protects dopaminergic neurons from death by proteasomal inhibition and the accumulation of alpha-synuclein.