Cerebrospinal fluid lysosomal enzymes and alpha‐synuclein in Parkinson's disease

Abstract

To assess the discriminating power of multiple cerebrospinal fluid (CSF) biomarkers for Parkinson's disease (PD), we measured several proteins playing an important role in the disease pathogenesis. The activities of β-glucocerebrosidase and other lysosomal enzymes, together with total and oligomeric α-synuclein, and total and phosphorylated tau, were thus assessed in CSF of 71 PD patients and compared to 45 neurological controls. Activities of β-glucocerebrosidase, β-mannosidase, β-hexosaminidase, and β-galactosidase were measured with established enzymatic assays, while α-synuclein and tau biomarkers were evaluated with immunoassays. A subset of PD patients (n = 44) was also screened for mutations in the β-glucocerebrosidase-encoding gene (GBA1). In the PD group, β-glucocerebrosidase activity was reduced (P < 0.05) and patients at earlier stages showed lower enzymatic activity (P < 0.05); conversely, β-hexosaminidase activity was significantly increased (P < 0.05). Eight PD patients (18%) presented GBA1 sequence variations; 3 of them were heterozygous for the N370S mutation. Levels of total α-synuclein were significantly reduced (P < 0.05) in PD, in contrast to increased levels of α-synuclein oligomers, with a higher oligomeric/total α-synuclein ratio in PD patients when compared with controls (P < 0.001). A combination of β-glucocerebrosidase activity, oligomeric/total α-synuclein ratio, and age gave the best performance in discriminating PD from neurological controls (sensitivity 82%; specificity 71%, area under the receiver operating characteristic curve = 0.87). These results demonstrate the possibility of detecting lysosomal dysfunction in CSF and further support the need to combine different biomarkers for improving the diagnostic accuracy of PD.

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

“…Lack of differences in the oligomeric-total ratio in contrast to two previous reports [8,18] might be due to lack of differences in CSF total-a-synuclein in our cohort. The large overlap among groups and the lack of association with iRBD cast doubt on CSF oligomeric-a-synuclein as a standalone diagnostic or premotor PD biomarker.…”

“…CSF levels of oligomeric-a-synuclein, believed to be a toxic a-synuclein fraction [17], have been found increased [8,14] or non-significantly different [18] in PD vs. controls, with increased oligomeric/total-a-synuclein ratio having been reported in two of these studies [8,18]. Allegedly, drop in CSF total-a-synuclein might reflect parenchymal sequestration of a-synuclein in Lewy-type lesions or an attempt of retaining the protein to maintain neuronal physiology, whereas increased clearance to CSF of soluble and toxic oligomers might account for raised CSF oligomeric-a-synuclein [1,2].…”

Genetic perspective on the role of the autophagy-lysosome pathway in Parkinson disease

“…It seems that the answer for both questions may be yes. There is a growing body of evidence that GBA activity is reduced not only in GBA-associated PD, but in sporadic PD as well, 74,196,197 suggesting that other genetic or environmental factors may lead to GBA impairment and to the subsequent pathological effect. One possible factor is SNCA itself, which may interact with and inhibit wild-type GBA.…”

Recent advances in biomarkers for Parkinson’s disease focusing on biochemicals, omics and neuroimaging

“…β-Glucocerebrosidase is a lysosomal hydrolase encoded by GBA1, whose mutations represent a recognized risk factor for PD. In a new study, it was found that β-glucocerebrosidase activity was reduced in CSF of PD patients (p < 0.05) [30]. A combination of β-glucocerebrosidase activity, oligomer/total α-synuclein ratio, and age gave the best performance in discriminating PD from neurological controls [sensitivity 82%; specificity 71%, area under the receiver operating characteristic curve (ROC) = 0.87], which demonstrates the possibility of detecting lysosomal dysfunction in CSF and further supports the need to combine different biomarkers for improving the diagnostic accuracy of PD [30].…”