Oligomeric and phosphorylated alpha-synuclein as potential CSF biomarkers for Parkinson’s disease

Abstract

BackgroundDespite decades of intensive research, to date, there is no accepted diagnosis for Parkinson’s disease (PD) based on biochemical analysis of blood or CSF. However, neurodegeneration in the brains of PD patients begins several years before the manifestation of the clinical symptoms, pointing to serious flaw/limitations in this approach.ResultsTo explore the potential use of alpha-synuclein (α-syn) species as candidate biomarkers for PD, we generated specific antibodies directed against wide array of α-syn species, namely total-, oligomeric- and phosphorylated-Ser129-α-syn (t-, o- and p-S129-α-syn). Next we sought to employ our antibodies to develop highly specific ELISA assays to quantify α-syn species in biological samples. Finally we verified the usefulness of our assays in CSF samples from 46 PD patients and 48 age-matched healthy controls. We also assessed the discriminating power of combining multiple CSF α-syn species with classical Alzheimer’s disease biomarkers. The combination of CSF o-/t-α-syn, p-S129-α-syn and p-tau provided the best fitting predictive model for discriminating PD patients from controls. Moreover, CSF o-α-syn levels correlated significantly with the severity of PD motor symptoms (r = -0.37).ConclusionOur new ELISA assays can serve as research tools to address the unmet need for reliable CSF biomarkers for PD and related disorders.Electronic supplementary materialThe online version of this article (doi:10.1186/s13024-016-0072-9) contains supplementary material, which is available to authorized users.

Increased levels of CSF total but not oligomeric or phosphorylated forms of alpha-synuclein in patients diagnosed with probable Alzheimer’s disease

“…CSF t-, o- and p-S129-α-syn levels were measured using our recently published ELISA assays28. Briefly, for measuring t-α-syn, a 384-well ELISA microplate was coated by overnight incubation at 4 °C with 0.1 μg/ml Syn-140 (sheep anti-α-syn polyclonal antibody) in 200 mM NaHCO 3 , pH 9.6 (50 μl/well).…”

Current state of Alzheimer’s fluid biomarkers

“…There are reports of increased CSF concentrations of α-synuclein oligomers in CSF of PD patients [132, 233, 364], and recent publications on sensitive assays that appear to detect the minute amounts of putative seeds of α-synuclein oligomers in CSF [86, 325]. …”

Dysregulation of Ubiquitin-Proteasome System in Neurodegenerative Diseases

“…Sporadic PD accounts for more than 90% of PD cases (Lang and Lozano, 1998), and only less than 10% of familial PD cases are caused by monogenic mutations (Benitez et al, 2016). Mutations in the gene encoding α-synuclein (Polymeropoulos et al, 1997; Helferich et al, 2015; Majbour et al, 2016; Schonherr et al, 2016) represent autosomal dominant familial PD, and mutations in genes encoding parkin (Kitada et al, 1998; Cha et al, 2015), UCHL1 (Leroy et al, 1998; Maraganore et al, 1999), DJ-1 (Bonifati et al, 2003), PINK1 (Valente et al, 2004), and LRRK2 (Zimprich et al, 2004; Saha et al, 2015) cause autosomal recessive familial PD.…”