Changes in endolysosomal enzyme activities in cerebrospinal fluid of patients with Parkinson's disease

Abstract

Parkinson's disease (PD) is characterized neuropathologically by the cytoplasmic accumulation of misfolded α-synuclein in specific brain regions. The endolysosomal pathway appears to be involved in α-synuclein degradation and, thus, may be relevant to PD pathogenesis. This assumption is further strengthened by the association between PD and mutations in the gene encoding for the lysosomal hydrolase glucocerebrosidase. The objective of the present study was to determine whether endolysosomal enzyme activities in cerebrospinal fluid (CSF) differ between PD patients and healthy controls. Activity levels of 6 lysosomal enzymes (β-hexosaminidase, α-fucosidase, β-mannosidase, β-galactosidase, β-glucocerebrosidase, and cathepsin D) and 1 endosomal enzyme (cathepsin E) were measured in CSF from 58 patients with PD (Hoehn and Yahr stages 1-3) and 52 age-matched healthy controls. Enzyme activity levels were normalized against total protein levels. Normalized cathepsin E and β-galactosidase activity levels were significantly higher in PD patients compared with controls, whereas normalized α-fucosidase activity was reduced. Other endolysosomal enzyme activity levels, including β-glucocerebrosidase activity, did not differ significantly between PD patients and controls. A combination of normalized α-fucosidase and β-galactosidase discriminated best between PD patients and controls with sensitivity and specificity values of 63%. In conclusion, the activity of a number of endolysosomal enzymes is changed in CSF from PD patients compared with healthy controls, supporting the alleged role of the endolysosomal pathway in PD pathogenesis. The usefulness of CSF endolysosomal enzyme activity levels as PD biomarkers, either alone or in combination with other markers, remains to be established in future studies.

Correlation between decreased CSF α-synuclein and Aβ1–42 in Parkinson disease

“…Emerging data on the detection of elevated levels of oligomeric and phosphorylated forms of CSF α-syn, along with changes in the levels of CSF lysosomal enzymes in PD indicates that these proteins could be useful biomarkers of pathology (Park, et al, 2011,Parnetti, et al, 2014a,Parnetti, et al, 2014b,Tokuda, et al, 2010,van Dijk, et al, 2013,Wang, et al, 2012). Measurement of other CSF proteins may yield additional biomarkers for PD, including proteins present in both the CSF and the cortical proteomes identified by proteomic analysis (Pan, et al, 2007).…”

Cerebrospinal fluid biomarkers in parkinsonian conditions: an update and future directions

“…A recent study showed that the combination of GCase activity, oligomeric/total α-Syn ratio and age discriminates best PD from neurological controls 89. However, in a Dutch cohort of de novo PD patients and healthy controls, there was a trend towards a reduction in CSF GCase activity 90. The usefulness of GCase as a potential biomarker in parkinsonian conditions needs to be evaluated in future studies that include additional neurodegenerative groups to PD.…”

Cerebrospinal fluid biochemical studies in patients with Parkinson's disease: toward a potential search for biomarkers for this disease

“…Studies measuring CSF levels of lysosomal hydrolases (involved in the α-Syn degradation) found decreased (Balducci et al, 2007), normal (van Dijk et al, 2013b), or increased (Parnetti et al, 2014a) β-hexosaminidase, increased cathepsin E (van Dijk et al, 2013b), decreased α-mannosidase (Balducci et al, 2007), decreased (Balducci et al, 2007) or normal β-mannosidase (Mollenhauer et al, 2011; van Dijk et al, 2013b), decreased α-fucosidase (van Dijk et al, 2013b), β-glucocerebrosidase decreased (Balducci et al, 2007; Parnetti et al, 2014a) or normal (van Dijk et al, 2013b), β-galactosidase increased (van Dijk et al, 2013b) or normal (Balducci et al, 2007; Parnetti et al, 2014a), and cathepsin D normal (van Dijk et al, 2013b) in PD patients compared with controls.…”