Low CSF Levels of Both α-Synuclein and the α-Synuclein Cleaving Enzyme Neurosin in Patients with Synucleinopathy

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.

Quantification of CSF biomarkers using an electrochemiluminescence-based detection system in the differential diagnosis of AD and sCJD

“…Interestingly, asynuclein, contrary to Tau and Ab42, is specifically regulated in sCJD. Although increased levels of a-synuclein have been reported in AD cases when compared to controls, these increases range from low to moderate and present no relevant clinical significance [34,38].…”

Correlates of cerebrospinal fluid levels of oligomeric- and total-α-synuclein in premotor, motor and dementia stages of Parkinson’s disease

“…Conversely, increased leakage to CSF might underlie their increase. Notably, high levels of both CSF total-a-synuclein and CSF s are being increasingly reported in Alzheimer's disease (AD) [16,37], and cortical s neurofibrillary pathology is not rare in PDD and correlates with cortical Lewy pathology [38]. In the light of all this and of the trend to low CSF total-a-synuclein in PD when controlling for high CSF s, it can be hypothesised that greater cortical pathology (including Alzheimer-type lesions in some instances) in the setting of advanced PD with cognitive impairment or dementia might result in increased leakage of intracellular proteins as a-synuclein and tau to CSF from neurons undergoing degeneration.…”

Blood and cerebrospinal fluid markers in Parkinson's disease: current biomarker findings

“…12 and plasma, [13][14][15] and decreased CSF α-synuclein levels in PD have now been demonstrated in a number of studies. 12,[16][17][18][19][20][21][22][23] Two of these studies examined patients with early PD, making it unlikely that results are simply associated with anti-PD medication effects. 22,23 These studies have raised hopes that α-synuclein could be a first diagnostic marker for PD.…”