Abstract
Neurosin is a protease that in vitro degrades α-synuclein, the main constituent of Lewy bodies found in brains of patients with synucleinopathy including Parkinson's disease (PD) and dementia with Lewy bodies (DLB). Several studies have reported reduced cerebrospinal fluid (CSF) levels of α-synuclein in synucleinopathy patients and recent data also proposes a significant role of α-synuclein in the pathophysiology of Alzheimer's disease (AD). To investigate potential links between neurosin and its substrate α-synuclein in vivo we used a commercially available sandwich ELISA and an in-house developed direct ELISA to quantify CSF levels of α-synuclein and neurosin in patients diagnosed with DLB, PD and PD dementia (PDD) versus AD patients and non-demented controls. We found that patients with synucleinopathy displayed lower CSF levels of neurosin and α-synuclein compared to controls and AD patients. In contrast, AD patients demonstrated significantly increased CSF α-synuclein but similar neurosin levels compared to non-demented controls. Further, CSF neurosin and α-synuclein concentrations were positively associated in controls, PD and PDD patients and both proteins were highly correlated to CSF levels of phosphorylated tau in all investigated groups. We observed no effect of gender or presence of the apolipoprotein Eε4 allele on neither neurosin or α-synuclein CSF levels. In concordance with the current literature our study demonstrates decreased CSF levels of α-synuclein in synucleinopathy patients versus AD patients and controls. Importantly, decreased α-synuclein levels in patients with synucleinopathy appear linked to low levels of the α-synuclein cleaving enzyme neurosin. In contrast, elevated levels of α-synuclein in AD patients were not related to any altered CSF neurosin levels. Thus, altered CSF levels of α-synuclein and neurosin in patients with synucleinopathy versus AD may not only mirror disease-specific neuropathological mechanisms but may also serve as fit candidates for future biomarker studies aiming at identifying specific markers of synucleinopathy.
Highlights
The neuronal protein a-synuclein has been the focus of interest in several recent studies on patients with neurodegenerative disorders [1]
In order to simplify the discussion around patients with synucleinopathies table 1 shows the demographic data of patients with dementia with Lewy bodies (DLB), Parkinsons’s disease (PD) and PD dementia (PDD) grouped into one group of patients with synucleinopathy (SYN)
Since correlation analysis revealed that cerebrospinal fluid (CSF) neurosin was significantly linked to age in the control group (r = 0.317, p = 0.022) and the mean age of the investigated diagnostic groups was significantly different, the statistical analyses was corrected for age
Summary
The neuronal protein a-synuclein has been the focus of interest in several recent studies on patients with neurodegenerative disorders [1]. The same study showed that the extracellular levels of a-synuclein in post mortem human brain homogenates were just as high as the a-synuclein intracellular levels [17] These novel findings in combination with the previous reports suggesting that the gradual spread of synucleinopathy, described in the PD brain [4], might be due to cell-to-cell transmission of a-synuclein [18,19] highly warrant investigations of the extracellular asynuclein breakdown mechanisms. All three groups found the protein to be expressed in human brain tissue and additional studies confirmed that neurosin exists in high concentrations in various biological fluids such as human breast milk, nipple aspirate fluid and CSF [24]. The a-synuclein degrading property of neurosin has convincingly been demonstrated in cell-free systems and in cultured cells [26,27] and additional in vitro studies have shown that phosphorylated a-synuclein is more resistant to neurosin degradation than non-phosphorylated a-synuclein [28]
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