In Parkinson's disease (PD) there is a critical need for validated biomarkers to make diagnosis and evaluate disease progression and therapeutic responses. Biomarkers may also provide insight into pathogenesis, and might therefore suggest possible novel targets for therapeutic intervention.
There is substantial evidence to suggest that the conversion of α-synuclein (α-syn) from soluble monomers to aggregated, insoluble forms in the brain is a key event in the pathogenesis of PD and related diseases. It has been shown that neuronal cells in culture constitutively secrete α-syn into the culture medium and that α-syn is normally present in cerebrospinal fluid (CSF) and peripheral plasma. We developed a specific ELISA system and found that PD patients had significantly lower α-syn levels in their CSF than the control groups. We then investigated the levels of α-syn oligomers in CSF using our own ELISA that can specifically detect α-syn oligomers. The levels of α-syn oligomers in CSF were higher in the PD group compared to the control group. The receiver operating characteristic curve analysis showed a sensitivity of 75.0% and a specificity of 87.5% for the diagnosis of PD. Our results demonstrate that levels of α-syn oligomers in CSF can be a useful biomarker for diagnosis of PD.
Protein degradation system in extracellular space is important in the pathogenesis of PD, because extracellular α-syn may move from neuron to neuron to propagate α-syn pathology. We previously reported that neurosin that is a trypsin-like serine protease predominantly expressed in the central nervous system can cleave α-syn. We also coexpressed α-syn with neurosin and demonstrated that α-syn was not cleaved within cells, but extracellular α-syn was degraded by secreted neurosin. Our data suggest that insufficient or abnormal extracellular cleavage of α-syn by neurosin might cause oligomerization and aggregation of α-syn.